Kidney injury molecule-1 (KIM-1): a novel kidney-specific injury molecule playing potential double-edged functions in kidney injury

doi:10.1016/j.trre.2010.02.002

Transplantation Reviews

Volume 24, Issue 3, July 2010, Pages 143-146

https://doi.org/10.1016/j.trre.2010.02.002 Get rights and content

Abstract

Kidney injury molecule-1 (KIM-1), a recently discovered transmembrane protein, is expressed in dedifferentiated proximal renal tubular epithelial cells in damaged regions. It may participate in the progress of renal injury or repair. Many studies have illustrated the different functions of KIM-1 in various renal diseases including protective functions in acute kidney injury and damaging functions in chronic kidney disease. Although, the exact functions of KIM-1 still remain unclear, some scientists speculate that KIM-1 is expected to be a therapeutic target for kidney injury. In this review, some of the known features and functions of KIM-1 are highlighted.

Introduction

Renal epithelial cell injury is the feature of many acute and chronic renal diseases. Kidney injury molecule-1 (KIM-1), a recently discovered transmembrane tubular protein, is undetectable in normal kidneys, but it is markedly induced in renal injury including acute kidney injury (AKI) and chronic kidney disease (CKD) [1], [2], [3]. Many studies indicate that KIM-1 is a sensitive and specific marker of kidney injury as well as a predictor of prognosis [4], [5]. In fact, KIM-1 is more than a noninvasive marker for kidney injury. A number of studies have demonstrated that KIM-1 may play a role in kidney injury and repair, although very little is known about the precise molecular mechanism that regulates these events [6], [7].

Section snippets

Structure of KIM-1

KIM-1 (also known as TIM-1—T-cell immunoglobulin and mucin-containing molecule) was originally discovered in a screen for molecules involved in the pathogenesis of AKI. Ichimura et al [1] first identified the complementary DNA for a type 1 membrane protein from postischemic rat kidney by representational difference analysis and called it kidney injury molecule-1. This gene encodes a type I cell membrane glycoprotein containing in its extracellular portion a 6-cysteine immunoglobulin-like domain

KIM expression location

The KIM-1 gene or protein expression is undetectable in normal kidney. In the injured kidney, KIM-1 messenger RNA is rapidly duplicated and protein is generated and localized at very high levels on the apical membrane of proximal tubule in the region where the tubule is most affected. The KIM-1 expression is absent in the glomerulus, peritubular interstitial cells, or inner medullary cells [1], [2]. In the experiment of kidney ischemia in rodents, KIM-1 was expressed predominantly in the S3

KIM-1 as a specific biomarker for kidney injury

In renal patients, KIM-1 is up-regulated in a variety of conditions including ischemia, nephrotoxic drugs, CKD, and acute/chronic renal transplant dysfunction. There are a growing number of studies that demonstrate the use of KIM-1 as a marker for kidney injury including AKI and chronic kidney injury. There are many characteristics of KIM-1 making it an ideal biomarker for kidney injury. For example, KIM-1 is not expressed in normal kidney but specifically expressed in injured proximal tubular

KIM-1 and AKI

In situ hybridization and immunohistochemistry revealed that KIM-1 was expressed in dedifferentiated and regenerative proximal tubular epithelial cells in damaged regions after toxic or ischemic injury, and KIM-1 colocalized with bromodeoxyuridine (a marker of proliferation ) and elastin (a marker of dedifferentiation). Therefore, KIM-1 may play a role in the regeneration process of tubular epithelial cells, through which it can help reconstitute a continuous epithelial layer [1], [7], [8].

Summary and prospect

Kidney injury molecule-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. Although the exact function of KIM-1 still remains unclear, the protective function of KIM-1 was reported mainly in AKI such as ischemic or toxic injury and the damaging function of KIM-1 was reported mainly in chronic renal diseases. So, we can hypothesize that KIM-1 may

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Exploration of zebrafish larvae as an alternative whole-animal model for nephrotoxicity testing
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Due to an increasing demand for testing of new and existing chemicals and legal restrictions for the use of animals, there is a strong need for alternative approaches to assess systemic toxicity. Embryonic and larval zebrafish (Danio rerio) are increasingly recognized as a promising alternative whole-animal model that may be able to overcome limitations of cell-based in vitro assays and bridge the gap between high-throughput in vitro screening and low-throughput in vivo tests in animals. Despite the relatively simple anatomical structure of the zebrafish larval kidney (pronephros) – composed of only two nephrons - the pronephros shares major functions and cell types with mammalian nephrons. Glomerular filtration begins at 48 h post fertilization. The aim of the present study was to investigate if early zebrafish larvae might be a suitable model for nephrotoxicity testing. On day 3 post fertilization, larval zebrafish were treated with selected nephrotoxins (aristolochic acid, cadmium chloride, potassium bromate, ochratoxin A, gentamicin) for 48 h. Histological evaluation of zebrafish larvae exposed to model nephrotoxins revealed tubule injury as evidenced by dilated tubules with loss of the brush border, tubule cell necrosis and disorganization of the tubular epithelium. These changes were most severe after treatment with gentamicin, which also impaired pronephros function as evidenced by reduced clearance of FITC-dextran. Whole-mount in situ hybridization showing loss of cdh17 expression revealed site-specific injury to the proximal tubule segment. Analysis of genes previously identified as novel biomarkers of kidney injury in mammals showed upregulation of the kidney injury marker genes heme oxygenase 1 (hmox1), clusterin (clu), secreted phosphoprotein/osteopontin (spp1), connective tissue growth factor (ctgf) and kim-1 (havcr-1) in response to nephrotoxin treatment, although the response of individual genes varied across compounds. Consistent with the severity of lesions and impaired kidney function, the most prominent gene expression changes occurred in larvae exposed to gentamicin. Overall, our results suggest that larval zebrafish may be a suitable alternative model organism for nephrotoxicity screening, yet further improvements and integration with quantitative in vitro to in vivo extrapolation will be needed to predict human toxicity.
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Citation Excerpt :
KIM-1 is a type 1 transmembrane protein that cannot be detected in normal kidney tissue and urine (Ichimura et al., 1998). However, it is expressed at very high levels in the proximal tubules shortly after kidney injury, including ischemic and toxic insults (Huo et al., 2010). Among kidney transplantation patients, higher urine KIM-1 levels are independently and differentially associated with a greater risk of adverse outcomes (Bansal et al., 2016).
Nephrotoxicity is the major adverse reaction to tacrolimus; however, the underlying mechanisms remain to be fully elucidated. Although several tacrolimus-induced nephrotoxicity animal models have been reported, most renal injury rat models contain factors other than tacrolimus. Here, we report the development of a new nephrotoxicity with interstitial fibrosis rat model induced by tacrolimus administration. Thirty Wistar rats were randomly divided into four groups: sham-operated (Sham), vehicle-treated ischemia reperfusion (I/R) injury (IRI), tacrolimus treated (TAC) and tacrolimus treated I/R injury (TAC + IRI). Rats subjected to IR injury and treated with tacrolimus for 2 weeks showed higher serum creatinine (Scr), blood urea nitrogen (BUN), serum magnesium (Mg) and serum potassium (K), indicating decreased renal function. In addition, tacrolimus treatment combined with IR injury increased histological injury (tubular vacuolation, glomerulosclerosis and interstitial fibrosis), as well as α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), and kidney injury molecule-1 (KIM-1) expression in the renal cortex. In summary, we have developed a tacrolimus-induced kidney injury rat model with interstitial fibrosis within 2 weeks by creating conditions mimicking renal transplantation via tacrolimus administration following ischemia-reperfusion.
Can serum Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule−1 help in decision making for surgery in antenatally dedected hydronephrosis
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Citation Excerpt :
NGAL is a protein from lipocalin family and it is reported that it may be an indicator for several renal diseases [18–20]. There are also studies in the literature reporting that the levels of KIM-1 and NGAL increase in serum and urine levels in obstructive nephropathy, ischemia or kidney injury due to nephrotoxic agents [15,21,22]. Conventional methods may not be sufficient to decide on surgery in the postnatal period in patients with hydronephrosis detected in the antenatal period.
Congenital obstructive uropathies are among leading reasons for renal failure in children. Answers to questions such as what the critical threshold of obstruction is or which degree of obstruction disrupts the development of the kidney still remain unclear. Several biomarkers such as Kidney Injury Molecule 1 (KIM-1) and Neutrophil Gelatinase Associated Lipocalin (NGAL) may help clinicians in the clinical evaluation and appropriate planning of the disease.
This study aimed to investigate whether serum and urinary KIM-1 and NGAL levels contribute to conventional methods in decision-making for surgery in the postnatal period of infants with antenatal hydronephrosis.
34 patients with the diagnosis of antenatal hydronephrosis were evaluated prospectively. Renal pelvis diameters of all patients were above 10 mm in the ultrasonography (USG). Patients underwent diuretic renal scintigraphy after neonatal period. Patients were divided into two groups as surgery or follow-up based on USG and scintigraphy findings. Blood and urine samples were collected at first visits in both groups and again at the 3. Postoperative month in the surgery group. Serum and urinary NGAL and KIM-1 levels were measured by ELISA method. Study data were compared through the Mann–Whitney U and Wilcoxon Signed-Ranks test.
There were 10 patients in the surgery group and 24 patients in the follow-up group. The age and gender did not differ between the groups. The surgery group had significantly higher median serum NGAL values (259.2 ng/mL) than that in the follow-up group (46.8 ng/mL, p = 0.028). The postoperative reduction of the median serum NGAL to 68.1 ng/mL compared to preoperative level was also found to be significant (p = 0.037) in the surgery group. Between the groups and within the surgery group no statistically significant difference was detected in terms of median urinary NGAL, and serum and urine KIM-1 levels.
USG and renal scintigraphy are frequently used in determining whether patients with antenatal hydronephrosis need surgical intervention in the postnatal period. Several new biomarkers might help clinicians in decision making for surgery. KIM-1 and NGAL levels can be measured both in urine and serum. To our knowledge, this is the only study where serum NGAL and KIM-1 levels were measured in patients with antenatal diagnosis. Small sample size, lack of long term findings and control group are limitations of our study.
Serum NGAL levels of patients with antenatal hydronephrosis may help in decision making on the surgical intervention.

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¹: Wenqian Huo and Keqing Zhang contribute equally to the article.

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Kidney injury molecule-1 (KIM-1): a novel kidney-specific injury molecule playing potential double-edged functions in kidney injury

Abstract

Introduction

Section snippets

Structure of KIM-1

KIM expression location

KIM-1 as a specific biomarker for kidney injury

KIM-1 and AKI

Summary and prospect

J Biol Chem

Kidney Int

J Biol Chem.

Trends Mol Med

Toxicol Appl Pharmacol

Kidney Int

Kidney Int

Immunity

Kidney Int

Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury

Am J Physiol Renal Physiol.

KIM-1/Tim-1: from biomarker to therapeutic target

Nephrol Dial Transplant

Biomarkers of acute kidney injury

Annu Rev Pharmacol Toxicol

Goering. Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium

Toxicol Sci

Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury

Am J Physiol.

Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinase and juxtamembrane region

J Am Soc Nephrol