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

2006 ◽  
Vol 290 (2) ◽  
pp. F517-F529 ◽  
Author(s):  
Vishal S. Vaidya ◽  
Victoria Ramirez ◽  
Takaharu Ichimura ◽  
Norma A. Bobadilla ◽  
Joseph V. Bonventre
Keyword(s):  
Renal Damage ◽  
Kidney Injury ◽  
Plasma Creatinine ◽  
Tubular Injury ◽  
Early Assessment ◽  
Preclinical Drug Development ◽  
High Throughput Method ◽  
Kidney Injury Molecule 1 ◽  
Pharmaceutical Agents ◽  
Time Point

Sensitive and specific biomarkers are needed to detect early kidney injury. The objective of the present work was to develop a sensitive quantitative urinary test to identify renal injury in the rodent to facilitate early assessment of pathophysiological influences and drug toxicity. Two mouse monoclonal antibodies were made against the purified ectodomain of kidney injury molecule-1 (Kim-1), and these were used to construct a sandwich Kim-1 ELISA. The assay range of this ELISA was 50 pg/ml to 5 ng/ml, with inter- and intra-assay variability of <10%. Urine samples were collected from rats treated with one of three doses of cisplatin (2.5, 5, or 7.5 mg/kg). At one day after each of the doses, there was an approximately three- to fivefold increase in the urine Kim-1 ectodomain, whereas other routinely used biomarkers measured in this study [plasma creatinine, blood urea nitrogen (BUN), urinary N-acetyl-β-glucosaminidase (NAG), glycosuria, proteinuria] lacked the sensitivity to show any sign of renal damage at this time point. When rats were subjected to increasing periods (10, 20, 30, or 45 min) of bilateral ischemia, there was an increasing amount of urinary Kim-1 detected. After only 10 min of bilateral ischemia, Kim-1 levels on day 1 were 10-fold higher (5 ng/ml) than control levels, whereas plasma creatinine and BUN were not increased and there was no glycosuria, increased proteinuria, or increased urinary NAG levels. Thus urinary Kim-1 levels serve as a noninvasive, rapid, sensitive, reproducible, and potentially high-throughput method to detect early kidney injury in pathophysiological studies and in preclinical drug development studies for risk-benefit profiling of pharmaceutical agents.

scholarly journals Are Tubular Injury Markers NGAL and KIM-1 Useful in Pediatric Neurogenic Bladder?

2021 ◽  
Vol 10 (11) ◽  
pp. 2353
Author(s):  
Joanna Bagińska ◽  
Agata Korzeniecka-Kozerska
Keyword(s):  
Neurogenic Bladder ◽  
Kidney Injury ◽  
Healthy Children ◽  
Tubular Injury ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Activity Assessment ◽  
Kidney Injury Molecule 1 ◽  
Tract Infections ◽  
Neutrophil Gelatinase

The lack of early biomarkers of renal damage in children with neurogenic bladder (NB) prompts us to investigate the role of promising proteins: neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). This prospective analysis was conducted on 58 children with NB and 25 healthy children. We assessed urinary levels of NGAL and KIM-1 in both groups. Age, sex, anthropometric measurements, activity assessment, renal function, and urodynamics parameters were analyzed. The differences between the median uNGAL and uKIM-1 in the NB group compared to control were recorded. However, only uNGAL levels were statistically significantly higher. Statistically significant correlation was found between gender, recurrent urinary tract infections, bladder trabeculation, its compliance, activity assessment, and uNGAL. To conclude, elevated levels of uNGAL may be considered a biomarker of tubular injury in children with NB due to MMC in contrast to uKIM-1.

scholarly journals Kidney injury molecule-1 expression predicts structural damage and outcome in histological acute tubular injury

Renal Failure ◽  
2019 ◽  
Vol 41 (1) ◽  
pp. 80-87 ◽  
Author(s):  
Jieru Cai ◽  
Xiaoyan Jiao ◽  
Weili Luo ◽  
Jing Chen ◽  
Xunhui Xu ◽  
...  
Keyword(s):  
Structural Damage ◽  
Kidney Injury ◽  
Tubular Injury ◽  
Kidney Injury Molecule 1

scholarly journals Gene deletion of the Na+-glucose cotransporter SGLT1 ameliorates kidney recovery in a murine model of acute kidney injury induced by ischemia-reperfusion

2019 ◽  
Vol 316 (6) ◽  
pp. F1201-F1210 ◽  
Author(s):  
Josselin Nespoux ◽  
Rohit Patel ◽  
Kelly L. Hudkins ◽  
Winnie Huang ◽  
Brent Freeman ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Proximal Tubule ◽  
Gene Deletion ◽  
Ischemia Reperfusion ◽  
Plasma Osmolality ◽  
Kidney Injury ◽  
Tubular Injury ◽  
Outer Medulla ◽  
Glucose Reabsorption ◽  
Kidney Injury Molecule 1

Renal Na+-glucose cotransporter SGLT1 mediates glucose reabsorption in the late proximal tubule, a hypoxia-sensitive tubular segment that enters the outer medulla. Gene deletion in mice ( Sglt1−/−) was used to determine the role of the cotransporter in acute kidney injury induced by ischemia-reperfusion (IR), including the initial injury and subsequent recovery phase. On days 1 and 16 after IR, absolute and fractional urinary glucose excretion remained greater in Sglt1−/− mice versus wild-type (WT) littermates, consistent with a sustained contribution of SGLT1 to tubular glucose reabsorption in WT mice. Absence of SGLT1 did not affect the initial kidney impairment versus WT mice, as indicated by similar increases on day 1 in plasma concentrations of creatinine and urinary excretion of the tubular injury marker kidney injury molecule-1 as well as a similar rise in plasma osmolality and fall in urine osmolality as indicators of impaired urine concentration. Recovery of kidney function on days 14/16, however, was improved in Sglt1−/− versus WT mice, as indicated by lower plasma creatinine, higher glomerula filtration rate (by FITC-sinistrin in awake mice), and more completely restored urine and plasma osmolality. This was associated with a reduced tubular injury score in the cortex and outer medulla, better preserved renal mRNA expression of tubular transporters ( Sglt2 and Na+-K+-2Cl– cotransporter Nkcc2), and a lesser rise in renal mRNA expression of markers of injury, inflammation, and fibrosis [kidney injury molecule-1, chemokine (C-C motif) ligand 2, fibronectin 1, and collagen type I-α1] in Sglt1−/− versus WT mice. These results suggest that SGLT1 activity in the late proximal tubule may have deleterious effects during recovery of IR-induced acute kidney injury and identify SGLT1 as a potential therapeutic target.

scholarly journals The Marker of Tubular Injury, Kidney Injury Molecule-1 (KIM-1), in Acute Kidney Injury Complicating Acute Pancreatitis: A Preliminary Study

2020 ◽  
Vol 9 (5) ◽  
pp. 1463 ◽  
Author(s):  
Justyna Wajda ◽  
Paulina Dumnicka ◽  
Witold Kolber ◽  
Mateusz Sporek ◽  
Barbara Maziarz ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Acute Pancreatitis ◽  
Serum Creatinine ◽  
Kidney Injury ◽  
Care Hospital ◽  
Tubular Injury ◽  
Fatty Acid Binding ◽  
Number Of Patients ◽  
Initial Symptoms ◽  
Kidney Injury Molecule 1

Acute pancreatitis (AP) may be associated with severe inflammation and hypovolemia leading to organ complications including acute kidney injury (AKI). According to current guidelines, AKI diagnosis is based on dynamic increase in serum creatinine, however, creatinine increase may be influenced by nonrenal factor and appears late following kidney injury. Kidney injury molecule-1 (KIM-1) is a promising marker of renal tubular injury and it has not been studied in AP. Our aim was to assess if urinary KIM-1 may be used to diagnose AKI complicating the early stage of AP. We recruited 69 patients with mild to severe AP admitted to a secondary care hospital during the first 24 h from initial symptoms of AP. KIM-1 was measured in urine samples collected on the day of admission and two subsequent days of hospital stay. AKI was diagnosed based on creatinine increase according to Kidney Disease: Improving Global Outcomes 2012 guidelines. Urinary KIM-1 on study days 1 to 3 was not significantly higher in 10 patients who developed AKI as compared to those without AKI and did not correlate with serum creatinine or urea. On days 2 and 3, urinary KIM-1 correlated positively with urinary liver-type fatty acid-binding protein, another marker of tubular injury. On days 2 and 3, urinary KIM-1 was higher among patients with systemic inflammatory response syndrome, and several correlations between KIM-1 and inflammatory markers (procalcitonin, urokinase-type plasminogen activator receptor, C-reactive protein) were observed on days 1 to 3. With a limited number of patients, our study cannot exclude the diagnostic utility of KIM-1 in AP, however, our results do not support it. We hypothesize that the increase of KIM-1 in AKI complicating AP lasts a short time, and it may only be observed with more frequent monitoring of the marker. Moreover, urinary KIM-1 concentrations in AP are associated with inflammation severity.

Tubular kidney injury molecule-1 in protein-overload nephropathy

2006 ◽  
Vol 291 (2) ◽  
pp. F456-F464 ◽  
Author(s):  
Mirjan M. van Timmeren ◽  
Stephan J. L. Bakker ◽  
Vishal S. Vaidya ◽  
Veronique Bailly ◽  
Theo A. Schuurs ◽  
...  
Keyword(s):  
Renal Damage ◽  
Smooth Muscle Actin ◽  
Kidney Injury ◽  
Spatial Relations ◽  
Tubular Damage ◽  
Double Labeling ◽  
Toxic Injury ◽  
Damage Repair ◽  
Tubulointerstitial Damage ◽  
Kidney Injury Molecule 1

Kim-1, a recently discovered membrane protein, is undetectable in normal kidneys but markedly induced in proximal tubules after ischemic and toxic injury. The function of Kim-1 is unclear, but it is implicated in damage/repair processes. The Kim-1 ectodomain is cleaved by metalloproteinases and detectable in urine. We studied Kim-1 in a nontoxic, nonischemic, model of tubulointerstitial damage caused by acute proteinuria. Uninephrectomized (NX) rats received daily (ip) injections of 2 g BSA (NX+BSA, n = 12) or saline (NX, n = 6) for 3 wk. Kidneys were stained for various damage markers by immunohistochemistry (IHC). Kim-1 mRNA (RT-PCR, in situ hybridization), protein (IHC, Western blotting), and urinary Kim-1 (Luminex) were determined. Spatial relations between Kim-1 and other damage markers were studied by double labeling IHC. NX+BSA rats developed massive proteinuria (1,217 ± 313 vs. 18 ± 2 mg/day in NX, P < 0.001) and significant renal damage. Kim-1 mRNA was upregulated eightfold in NX+BSA (ratio Kim-1/β-actin, 4.08 ± 2.56 vs. 0.52 ± 0.64 in NX, P < 0.001) and localized to damaged tubules. Kim-1 protein expression was markedly induced in NX+BSA (2.46 ± 1.19 vs. 0.39 ± 0.10% staining/field in NX, P < 0.001). Urinary Kim-1 was significantly elevated in NX+BSA (921 ± 592 vs. 87 ± 164 pg/ml in NX, P < 0.001) and correlated with tissue Kim-1 expression ( r = 0.66, P =0.02). Kim-1 protein was found at the apical membrane of dilated nephrons. Kim-1 expression was limited to areas with inflammation (MØ), fibrosis (α-smooth muscle actin), and tubular damage (osteopontin), and only occasionally with tubular dedifferentiation (vimentin). These results implicate involvement of Kim-1 in the pathogenesis of proteinuria-induced renal damage/repair. Urinary Kim-1 levels may serve as a marker of proteinuria-induced renal damage.

scholarly journals Evaluation of Fetal and Maternal Vancomycin-Induced Kidney Injury during Pregnancy in a Rat Model

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Medha D. Joshi ◽  
Gwendolyn M. Pais ◽  
Jack Chang ◽  
Khrystyna Hlukhenka ◽  
Sean N. Avedissian ◽  
...  
Keyword(s):  
Animal Studies ◽  
Renal Damage ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Tissue Homogenate ◽  
Tandem Mass ◽  
Pregnant Rats ◽  
Liquid Chromatography Tandem Mass ◽  
Kidney Injury Molecule 1 ◽  
Rat Pup

ABSTRACT Previous literature suggests that maternal vancomycin crosses the placental barrier to the fetus. Further, early animal studies indicated that kidney injury was not observed in the progeny. These studies were conducted prior to the availability of sensitive biomarkers for kidney injury. Therefore, a previous finding of no renal damage to the infant may be misleading. Vancomycin was administered intravenously to pregnant rats at a dose of 250 mg/kg of body weight/day (N = 6 per trimester) on three consecutive gestational days (GD) during trimesters 1, 2, and 3 (T1, T2, and T3, respectively) in three independent cohorts. The dams carried to term and delivered vaginally on GD 21. Kidneys were harvested from dams and pups and homogenized. Samples were prepared by protein precipitation and injected in a liquid chromatography tandem mass spectrometer, and vancomycin was quantified. The kidney tissue homogenate from dams and pups were analyzed for kidney injury molecule-1 (KIM-1). As trimesters progressed, the quantity of vancomycin increased linearly in the kidneys of both rat dams and pups (P < 0.0001 for T1 and T3, P < 0.0001 for T2 and T3, and P < 0.0001 for T3 and T3 control for both rat dams and pups). KIM-1 concentrations in pup kidneys were significantly higher when dams were administered vancomycin in trimesters 1 (P = 0.0001) and 2 (P = 0.0024) than in controls in trimester 3. Data demonstrate persistence of vancomycin in maternal and rat pup kidneys in all three trimesters of pregnancy with associated damage to the kidney, as indicated by expression of KIM-1.

scholarly journals Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

2013 ◽  
Vol 304 (11) ◽  
pp. R951-R958 ◽  
Author(s):  
Andrea Soljancic ◽  
Arnaldo Lopez Ruiz ◽  
Kiran Chandrashekar ◽  
Rodrigo Maranon ◽  
Ruisheng Liu ◽  
...  
Keyword(s):  
Renal Dysfunction ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Serum Testosterone ◽  
Protective Role ◽  
Male Rats ◽  
Plasma Creatinine ◽  
Acute Ischemia ◽  
Kidney Injury Molecule 1

Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease, in general. In the present study, we tested the hypothesis that I/R of the kidney reduces serum testosterone, and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 h after reperfusion that remained at 24 h. Acute infusion of testosterone 3 h after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 h, prevented the reduction in outer medullary blood flow, and attenuated the increase in intrarenal TNF-α and the decrease in intrarenal VEGF at 48 h. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 h than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney, whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol.

scholarly journals Proximal Tubular Injury in Medullary Rays Is an Early Sign of Acute Tacrolimus Nephrotoxicity

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Diane Cosner ◽  
Xu Zeng ◽  
Ping L. Zhang
Keyword(s):  
Immunosuppressive Agents ◽  
Elevated Serum ◽  
Kidney Injury ◽  
Serum Levels ◽  
Proximal Tubules ◽  
Solid Organ ◽  
Tubular Injury ◽  
Proximal Tubular ◽  
Normal Light ◽  
Kidney Injury Molecule 1

Tacrolimus (FK506) is one of the principal immunosuppressive agents used after solid organ transplantations to prevent allograft rejection. Chronic renal injury induced by tacrolimus is characterized by linear fibrosis in the medullary rays; however, the early morphologic findings of acute tacrolimus nephrotoxicity are not well characterized. Kidney injury molecule-1 (KIM-1) is a specific injury biomarker that has been proven to be useful in the diagnosis of mild to severe acute tubular injury on renal biopsies. This study was motivated by a patient with acute kidney injury associated with elevated serum tacrolimus levels in whom KIM-1 staining was present only in proximal tubules located in the medullary rays in the setting of otherwise normal light, immunofluorescent, and electron microscopy. We subsequently evaluated KIM-1 expression in 45 protocol and 39 indicated renal transplant biopsies to determine whether higher serum levels of tacrolimus were associated with acute segment specific injury to the proximal tubule, as reflected by KIM-1 staining in the proximal tubules of the cortical medullary rays. The data suggest that tacrolimus toxicity preferentially affects proximal tubules in medullary rays and that this targeted injury is a precursor lesion for the linear fibrosis seen in chronic tacrolimus toxicity.

scholarly journals Kidney injury molecule-1 identifies antemortem injury in postmortem adult and fetal kidney

2018 ◽  
Vol 315 (6) ◽  
pp. F1637-F1643 ◽  
Author(s):  
Wenqing Yin ◽  
Ping L. Zhang ◽  
Jacqueline K. Macknis ◽  
Fan Lin ◽  
Joseph V. Bonventre
Keyword(s):  
Serum Creatinine ◽  
Tissue Damage ◽  
Kidney Injury ◽  
Postmortem Examination ◽  
Tubular Injury ◽  
Fetal Kidney ◽  
Pulmonary Alveoli ◽  
Kidney Injury Molecule 1 ◽  
Postmortem Autolysis

There is currently no technique to unambiguously diagnose antemortem kidney injury on postmortem examination since postmortem tissue damage and autolysis are common. We assessed the ability to detect kidney injury molecule-1 (KIM-1) expression in adult and fetal kidneys examined at autopsy. In adult kidneys ( n = 52 subjects), we found that the intensity of KIM-1 staining significantly correlated with the antemortem level of serum creatinine, and this was independent of the extent of tissue autolysis. In addition, kidneys from a total of 52 fetal/neonatal subjects, 30 stillborns and 22 liveborns, were assessed for KIM-1 staining. Given that serum creatinine is unreliable and often unavailable in fetuses and newborns, we assessed preterminal hypoxia in fetuses by the presence of squames in pulmonary alveoli and by required intubation. KIM-1 expression correlated with these clinical indexes of hypoxia. The expression of KIM-1 was seen in a majority of the fetal and neonatal autopsy kidneys (77%, 40/52) as early as 16 wk of gestation, even in the presence of autolysis. Thus KIM-1 is a specific and stable marker of antemortem tubular injury in kidneys of adults and fetuses despite postmortem autolysis.

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