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Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes.

ABSTRACT: Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5-15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.

SUBMITTER: Sabbisetti VS

PROVIDER: S-EPMC4178434 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes.

Sabbisetti Venkata S VS Waikar Sushrut S SS Antoine Daniel J DJ Smiles Adam A Wang Chang C Ravisankar Abinaya A Ito Kazumi K Sharma Sahil S Ramadesikan Swetha S Lee Michelle M Briskin Rebeccah R De Jager Philip L PL Ngo Thanh Thu TT Radlinski Mark M Dear James W JW Park Kevin B KB Betensky Rebecca R Krolewski Andrzej S AS Bonventre Joseph V JV

Journal of the American Society of Nephrology : JASN 20140605 10

Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed an ...[more]

PMID: 24904085

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Project description:Background and objectivesElevated levels of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are associated with negative outcomes in CKD. Our study aimed to explore the prognostic accuracy of blood levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for progression to ESRD, major adverse cardiovascular events, and death in a large cohort of adult patients with all-cause nondialysis-dependent CKD stages 3-5. We considered whether these factors improve prediction in relation to traditional biomarkers and clinical parameters.Design, setting, participants, & measurementsKidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were measured on baseline plasma samples from 1982 patients who were recruited to the Chronic Renal Insufficiency Standards Implementation Study between the start of June of 2002 and the start of June of 2013. Associations with study end points were assessed using Cox regression models, receiver operator characteristic curve analyses, and reclassification statistics.ResultsOver a median follow-up of 29.5 months (interquartile range, 14.9-53.5), 21.6% of patients progressed to ESRD, 27% died, and 6.6% suffered a major adverse cardiovascular event. Higher blood levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were independently associated with a greater risk for ESRD (hazard ratio, 1.25; 95% confidence interval, 1.10 to 1.43; P<0.001 and hazard ratio, 1.35; 95% confidence interval, 1.14 to 1.59; P?0.001, respectively, per 1 SD higher biomarker concentration). There was no association with risk for cardiovascular events or death. The addition of biomarkers to our baseline risk model of traditional clinical characteristics and laboratory parameters did not significantly improve model discrimination or risk reclassification.ConclusionsIn patients with moderate to severe CKD, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin blood levels are independent risk factors for progression to ESRD. Additional studies are needed to establish the utility and cost-effectiveness of these novel biomarkers in the clinical setting.

Project description:BackgroundChronic kidney disease (CKD) is age-related disease, and decreased renal function is associated with the premature aging of T cells and increased incidence of other age-related diseases. However, the relationship between T cell senescence and CKD progression remains unclear. Here, we investigated the relationship between T cell senescence, as indicated by decreased thymic output and increased proportion of highly differentiated CD28- T cells, and CKD progression.ResultsA total of 175 patients with non-dialysis-dependent CKD were enrolled in this study. Thymic output was assessed based on the CD45RA+CD31+CD4+ cell (recent thymic emigrant [RTE]) counts (RTEs) (/mm3) and the proportion of RTE among CD4+ T cells (RTE%). Highly differentiated T cells were assessed based on the proportion of CD28- cells among CD4+ T cells (CD28-/CD4+) and CD28- cells among CD8+ T cells (CD28-/CD8+). The primary outcome was estimated glomerular filtration rate (eGFR) decline of ≥40% or initiation of renal replacement therapy. The association between T cell senescence and renal outcomes was examined using Cox proportional hazards models and restricted cubic splines. The median age was 73 years, 33% were women, and the median eGFR was 26 mL/min/1.73 m2. The median RTEs, RTE%, CD28-/CD4+, and CD28-/CD8+ were 97.5/mm3, 16.2, 5.3, and 49.7%, respectively. After a median follow-up of 1.78 years, renal outcomes were observed in 71 patients. After adjusting for age, sex, eGFR, proteinuria, diabetes, and cytomegalovirus seropositivity, decreased RTEs, which corresponded to decreased thymic output, significantly and monotonically increased the risk of poor renal outcome (p = 0.04), and decreased RTE% and increased highly differentiated CD28-/CD4+ T cells also tended to monotonically increase the risk (p = 0.074 and p = 0.056, respectively), but not CD28-/CD8+ T cells.ConclusionsDecreased thymic output in CKD patients, as well as increased highly differentiated CD4+ T cells, predicted renal outcomes. Thus, the identification of patients prone to CKD progression using T cell senescence, particularly decreased RTE as a biomarker, may help to prevent progression to end-stage kidney disease.

Project description:Background Ischemia during kidney transplant causes chronic allograft injury and adversely affects outcome, but the underlying mechanisms are incompletely understood. In tumors, oxygen shortage reduces the DNA demethylating activity of the ten-11 translocation (TET) enzymes, yielding hypermethylated genomes that promote tumor progression. We investigated whether ischemia similarly induces DNA hypermethylation in kidney transplants and contributes to chronic injury.Methods We profiled genome-wide DNA methylation in three cohorts of brain-dead donor kidney allograft biopsy specimens: a longitudinal cohort with paired biopsy specimens obtained at allograft procurement (preischemia; n=13), after implantation and reperfusion (postischemia; n=13), and at 3 or 12 months after transplant (n=5 each); a cross-sectional cohort with preimplantation biopsy specimens (n=82); and a cross-sectional cohort with postreperfusion biopsy specimens (n=46).Results Analysis of the paired preischemia and postischemia specimens revealed that methylation increased drastically in all allografts on ischemia. Hypermethylation was caused by loss of 5-hydroxymethylcytosine, the product of TET activity, and it was stable 1 year after transplant. In the preimplantation cohort, CpG hypermethylation directly correlated with ischemia time and for some CpGs, increased 2.6% per additional hour of ischemia. Hypermethylation preferentially affected and reduced the expression of genes involved in suppressing kidney injury and fibrosis. Moreover, CpG hypermethylation in preimplantation specimens predicted chronic injury, particularly fibrosis and glomerulosclerosis, 1 year after transplant. This finding was validated in the independent postreperfusion cohort, in which hypermethylation also predicted reduced allograft function 1 year after transplant, outperforming established clinical variables.Conclusions We highlight a novel epigenetic basis for ischemia-induced chronic allograft injury with biomarker potential.

Dataset Information

Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes.

Publications

Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes.

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