UNASSIGNED: Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD.
UNASSIGNED: Prospective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS]).
UNASSIGNED: Adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and without diabetes in the ARIC, REGARDS, and MESA studies.
UNASSIGNED: Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1.
UNASSIGNED: Incident CKD or end-stage kidney disease.
UNASSIGNED: Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts.
UNASSIGNED: 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m2. In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31).
UNASSIGNED: Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts.
UNASSIGNED: In 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.
This study analyzed 3 cohorts (ARIC, MESA, and REGARDS) of adults without diabetes or prevalent chronic kidney disease (CKD) to determine the associations of 5 urinary biomarkers of kidney tubulointerstitial health with incident CKD, independent of traditional measures of kidney health. Meta-analysis of results from all 3 cohorts suggested that higher baseline levels of urine alpha-1-microglobulin were associated with incident CKD at follow-up. Results from individual cohorts suggested that in addition to alpha-1-microglobulin, monocyte chemoattractant protein-1, kidney injury molecule-1, and epidermal growth factor may also be associated with the development of CKD. These findings underscore the importance of kidney tubule interstitial health in defining risk of CKD independent of creatinine and urine albumin.

Mancozeb is a widely-used, broad-spectrum contact dithiocarbamate fungicide. Dithiocarbamates are known to trans-chelate metals. This study was designed to evaluate the potential of Mancozeb to mobilize and bioaccumulate essential trace metals in various tissues. Long-Evans rats were orally gavaged with 0, 50, or 100 mg/kg/day of Mancozeb for 28 days. Mancozeb caused a significant increase in copper and manganese in the hippocampus and manganese in the liver. Exceedingly higher level of copper was detected in the renal cortex using ICP-OES in both dose groups. This was confirmed histologically in the tubular epithelial cells. In addition, copper-associated protein levels were also increased. Copper bioaccumulation in the renal cortex was accompanied by oxidative damage and tubular insult indicated by increased 4-HNE, KIM-1, and NGAL immunoreactivity. These findings demonstrate that low-dose Mancozeb exposure is a potential risk for kidney injury due to copper overload and warrants further in vivo and human population-based investigations.

OBJECTIVE: Hyperuricemia may lead to silent tissue damage and increase the risk of some diseases, including kidney diseases. Increased serum uric acid concentration induces inflammatory pathways and promotes kidney damage. This study aimed to determine whether hyperuricemia influences the levels of urinary kidney injury markers in children and adolescents with hyperuricemia, assessed by the urinary concentrations of interleukin-18, a biomarker of inflammation, and kidney injury molecule-1 (KIM-1), a biomarker of kidney injury.
METHODS: The study included 73 children and adolescents (32 males and 41 females) aged 2-18 years. They were divided into two groups: hyperuricemia (HU) group (n ​= ​48) and normouricemia - reference group (R) (n ​= ​25). The concentrations of urinary interleukin-18 and KIM-1 were measured using an ELISA kit and were normalized for urinary creatinine (cr.) concentration.
RESULTS: The median interleukin-18/cr. Levels in the HU group were significantly higher than in the R group (median, Q1-Q3) 21.83 (11.32-35.96) and 12.68 (7.11-24.04), respectively, (p ​< ​0.05). The KIM-1/cr. in the HU group and the R group were (median, Q1-Q3) 0.79 (0.45-1.03) and 0.81 (0.59-1.01), respectively, and the difference was not significant. KIM-1/cr. did not differ between the groups. Interleukin-18/cr. ratio correlated positively with serum uric acid concentration (r ​= ​0.24, p ​< ​0.05).
CONCLUSIONS: Interleukin-18/cr., but not KIM-1/cr. was higher in children with hyperuricemia. Hyperuricemia results in increased IL-18 in urine, in absence of other markers of kidney injury, suggesting inflammation in the kidney. Additional studies on the adults should be done, to confirm this hypothesis.

A variety of urinary markers of the renal disease show promise for the identification of glomerular and tubular damage and monitoring treatment. Most of the markers are currently not widely available, and all could benefit from further study. This review summarizes recent studies on urinary biomarkers of renal disease in dogs and cats.

BACKGROUND: Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein expressed predominantly on the proximal tubular epithelium.
OBJECTIVE: We wanted to see if there was a critical time for increased tubular damage and its related biomarker, KIM-1 mRNA, and protein expressions during the first 24 h of ischemia-reperfusion injury.
METHODS: An Experimental research used five male Rattus Norvegicus rats in each group. Bulldog clamp was used to clamp renal arteries and veins to create renal ischemia. Immunohistochemistry was used for the analysis of KIM-1 protein expression. While Tubular Injury Score was examined by Histopathology. RT-PCR was used for KIM-1 mRNA expression.
RESULTS: Tubular Injury Score (TIS) was significantly higher in ischemia than control. TIS remained similar after IR 30 min, peaked at IR 2 h, and decreased to the level of IR 30 min at IR 24 h.The KIM-1 mRNA expression was also higher in ischemia than in control. Similarly, KIM-1 mRNA expression increased more after IR 30 min, IR 2 h, and IR 24 h.The KIM-1 protein expression was higher in ischemia than in control. KIM-1 protein increased more after IR 30 min, IR for 2 h, and remained similar at IR for 24 h.KIM-1 mRNA and protein expressions at IR 2 h were significantly different compared to ischemia but not significantly different compared to that in IR 24 h.
CONCLUSIONS: KIM-1 mRNA and protein expressions increased within 24 h IR with the critical time was in the 2 h IR.

Cadmium exposure is associated with chronic kidney disease (CKD), but the optimal biomarker for early cadmium-associated nephrotoxicity in low-level exposure has not yet been established. We conducted a cross-sectional investigation involving 167 CKD patients stratified according to tertiles of urinary cadmium levels (UCd), in which enzyme-linked immunosorbent assay (ELISA)-measured novel renal biomarkers were utilized to assess the extent of renal injury associated with cadmium burden. In the analyses, urinary kidney injury molecule-1 (KIM-1) levels and age were the independent factors positively correlated with UCd after adjusting for covariates in non-dialysis-dependent CKD patients (high vs. low UCd, odds ratio (95% confidence interval), 1.0016 (1.0001-1.0032), p = 0.043, and 1.0534 (1.0091-1.0997), p = 0.018). Other conventional and novel renal biomarkers, such as serum creatinine, estimated glomerular filtration rate, CKD staging, urinary protein/creatinine ratio, urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), and urinary epidermal growth factor (EGF) were not independently correlated with UCd in the analyses. In conclusion, our study found that the ELISA-measured urinary KIM-1 level could serve as an early renal injury marker in low-level cadmium exposure for non-dialysis-dependent CKD patients. In addition, age was an independent factor positively associated with UCd in this population.

UNASSIGNED: Kidney injury molecule-1 (KIM-1) and periostin (POSTN) are proximal and distal tubule injury biomarkers. We tested whether baseline urine KIM-1/creatinine (uKIM-1/cr) and/or uPOSTN/cr correlated with disease severity or improved a remission prediction model.
UNASSIGNED: Baseline uKIM1/cr and uPOSTN/cr were measured on spot urine samples from immunosuppression-free patients enrolled in Nephrotic Syndrome Study Network until December 15, 2014. Urine protein/creatinine (UPCR) and albumin/creatinine (UACR) were measured at baseline, 4 months, and until last follow-up. Glomerular and tubulointerstitial (TI) expression arrays were analyzed from a baseline research renal biopsy core collected during a clinically indicated biopsy.Renal diagnoses were centrally confirmed, sections scanned, and measured morphometrically. Correlations between baseline uKIM-1/cr and uPOSTN/cr and UPCR, UACR, histopathologic features, glomerular and TI KIM-1 and POSTN expression levels, and renal outcomes were assessed.
UNASSIGNED: Baseline uKIM-1/cr correlated with UPCR and UACR, and were associated with complete remission after adjustment for proteinuria, histopathologic diagnosis, and treatment. Baseline uKIM-1/cr also correlated with degree of foot process effacement and acute tubular injury. Glomerular and TI KIM-1 expression levels correlated with UPCR and UACR. Higher TI KIM-1 expression levels correlated with interstitial fibrosis, tubular atrophy, and global glomerulosclerosis, while glomerular KIM-1 expression correlated with time to remission. Findings for POSTN were of lesser statistical strength.
UNASSIGNED: Lower baseline uKIM-1/cr values were associated with more rapid time to complete remission after adjusting for proteinuria, histopathologic diagnosis, and treatment. Increased TI KIM-1 expression levels in proteinuric states were associated with chronic morphological injury; lower glomerular expression levels were associated with a greater potential for proteinuria reversibility.

Kidney injury molecule-1 (KIM-1), also known as T cell immunoglobulin and mucin domain 1 (TIM-1), is a transmembrane glycoprotein expressed on proximal tubule epithelia during acute kidney injury (AKI). Extracellular domain of KIM-1 undergoes spontaneous and activated ectodomain shedding into urine and blood via metalloproteases. Soluble KIM-1 (blood and urinary) is a reliable clinical biomarker of proximal tubular injury, but the biological significance of shedding remains unknown. The aim of this study was to identify the specific shedding enzyme and the proteolytic cleavage site of murine KIM-1, followed by the characterization of its functional relevance. In this regard, isoleucine (I) I202 was identified as the potential cleavage site. Mutation of isoleucine I202 to glutamine (I202Q) or alanine (I202A) significantly reduced both constitutive and induced KIM-1 shedding and ultimately efferocytosis. It was also uncovered that ADAM10 is the major sheddase that mediates the proteolytic cleavage of murine KIM-1. In addition, ADAM10-induced KIM-1 shedding was required for efficient phagocytic clearance of apoptotic cells. Importantly, the findings that the addition of exogenous shed KIM-1 rescued the phagocytic impairment suggest that shed KIM-1 is capable of modulating efferocytosis of apoptotic bodies and could represent a potential functional role of the soluble ectodomain KIM-1 during AKI.

OBJECTIVE: This study aimed to investigate the clinical significance of urinary kidney injury molecule-1 (KIM-1) to monitor renal function in patients with obstructive unilateral ureteral calculi.
METHODS: Kidneys of 12 male C57BL/6J mice, as well as their urine and plasma specimens, were extracted to detect KIM-1 expressions 24 h after unilateral ureteral obstruction (UUO) construction or sham surgery. Meanwhile, a cohort of 89 patients with unilateral ureteral calculi was retrospectively reviewed. 46 of which received double-J ureteral stent indwelling (group 1) and the remaining 43 were treated conservatively (group 2). Urinary KIM-1 levels in the baseline, 2 h and 1 day after treatments were analyzed.
RESULTS: KIM-1 expressions were dramatically higher in mice underwent UUO surgery when compared with the sham group. Clinical data showed urinary KIM-1 levels decreased as time went by for patients in group 1 (1.787 ± 1.081 ng/mL for baseline, 1.668 ± 1.162 ng/mL for 2 h and 0.935 ± 0.526 ng/mL for 1 day after operation; p = 0.0001). Nevertheless, for those in group 2, a mild increase (1.659 ± 0.997 ng/mL, 1.691 ± 0.872 ng/mL and 1.675 ± 0.911 ng/mL, correspondingly; p = 0.9869) was observed. Additionally, a urinary KIM-1 value of 1.04 ng/mL had a sensitivity of 83.1% and specificity of 62.5% to predict the presence of hydronephrosis (95% CI: 0.641-0.873, AUC: 0.757, p < 0.001).
CONCLUSIONS: Urinary KIM-1 is a sensitive biomarker of post-renal acute kidney injury (AKI) and might predict the presence of hydronephrosis. It can be used as an effective surrogate to monitor renal function.

To investigate heavy metal exposure in an industrial zone vs. a living quarter in Shanghai and explore the relationship between the heavy metal source and urine cadmium (Cd) and early kidney damage. Blood lead and urine Cd, manganese (Mn), mercury (Hg), arsenic (As) and EKD indexes were compared between residents in Exposure group (n = 168) and Control group (n = 168). It was found that PM2.5 level in Exposure group was significantly higher than that in Control group, and serum Cys-C and urine Cd, NAG, mAlb, KIM-1 and Cd-MT levels in Exposure group were also significantly higher than those in Control group, suggesting that differences in urine Cd and heavy metal levels between the residents of the two groups may be due to different PM2.5 concentrations in the environments of the two areas. Cd accumulation within the human body can induce kidney damage, probably through its potential hazard to the proximal tubular epithelial cells.