• Graft evaluation
• Kidney graft function
• Kidney transplantation
• Non-invasive diagnosis
• Proteomics

Tubular injury biomarkers are not individually strong predictors of 3-month post-cisplatin CKD. When combined with clinical measures, tubular injury biomarkers can predict post-therapy hypertension and identify high-risk patients.

Urine kidney injury biomarkers measured during cisplatin therapy may identify patients at risk of adverse subsequent kidney outcomes. We examined relationships between tubular injury biomarkers collected early (early visit [EV]: first or s econd cisplatin cycle) and late (late visit: last or second-last cisplatin cycle) during cisplatin therapy, with 3-month post-cisplatin CKD and hypertension (HTN).

We analyzed data from the Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment Nephrotoxicity study, a 12-center prospective cohort study of 159 children receiving cisplatin. We measured urine neutrophil gelatinase-associated lipocalin (NGAL)/creatinine, kidney injury molecule-1/creatinine, tissue inhibitor of metalloproteinase-2 (TIMP-2), and insulin-like growth factor-binding protein 7 (IGFBP-7) (TIMP-2 and IGFBP-7 expressed as their product, ng/ml2/1000) at an EV and late visit during cisplatin therapy with preinfusion, postinfusion, and hospital discharge sampling. Area under the curve (AUC) was calculated for biomarkers to detect 3-month post-cisplatin CKD (Kidney Disease Improving Global Outcomes guidelines: low eGFR or elevated urine albumin-to-creatinine ratio for age) and HTN (three BPs; per American Academy of Pediatrics guidelines).

At median follow-up of 90 days, 52 of 118 patients (44%) and 17 of 125 patients (14%) developed CKD and HTN, respectively. Biomarker prediction for 3-month CKD was low to modest; NGAL combined with kidney injury molecule-1 at EV discharge yielded the highest AUC (0.67; 95% confidence interval, 0.57 to 0.77). Biomarker prediction of 3-month HTN was stronger, but modest; the highest AUC was from combining EV preinfusion NGAL and TIMP-2×IGFBP-7 (0.71; 95% confidence interval, 0.62 to 0.80). When EV preinfusion NGAL and TIMP-2×IGFBP-7 were added to the 3-month HTN clinical predictive model, AUCs increased from 0.81 (0.72 to 0.91) to 0.89 (0.83 to 0.95) (P < 0.05).

Tubular injury biomarkers we studied were individually not strong predictors of 3-month post-cisplatin kidney outcomes. Adding biomarkers to existing clinical prediction models may help predict post-therapy HTN and identify higher kidney-risk patients.

• aki
• bp
• ckd
• cisplatin
• cisplatin nephrotoxicity
• hypertension
• kidney disease
• nephrotoxicity
• pediatric nephrology
• renal injury

• Humans
• Cisplatin/adverse effects
• Biomarkers/blood
• Child
• Renal Insufficiency, Chronic/diagnosis
• Hypertension
• Kidney Tubules/pathology
• Kidney Tubules/metabolism
• Kidney Tubules/drug effects
• Female
• Male
• Child, Preschool
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Adolescent
• Hepatitis A Virus Cellular Receptor 1/metabolism

• Doctoral Training Bursary Fonds de Recherche du Québec - Santé
• Scholar Award Michael Smith Foundation for Health Research

• Chronic renal allograft dysfunction
• Extracellular regulated protein kinase 1/2
• Inflammation
• Lentivirus encoding TIMP2-targeting shRNA vector
• Tissue inhibitor of metalloproteinase-2

• Animals
• Rats
• Allografts/metabolism
• Fibrosis
• Inflammation
• Kidney Transplantation
• MAP Kinase Signaling System
• NF-kappa B/metabolism
• Rats, Inbred F344
• Rats, Inbred Lew
• Signal Transduction
• Tissue Inhibitor of Metalloproteinase-2/genetics
• Tissue Inhibitor of Metalloproteinase-2/metabolism

• CCL2
• Chronic kidney disease progression
• EGF
• NGAL
• TGF-α
• Urinary biomarkers

• Panax notoginseng rhizomes
• apoptosis
• inflammatory response
• network pharmacology
• renal ischemia–reperfusion injury

This study provided innovatory data regarding the role of EMMPRIN in long-term renal graft function and renal biopsy specimens in the form of interstitial fibrosis/tubular atrophy. The main cause of renal fibrosis is identified to be the activation and accumulation of fibroblasts and myofibroblasts in the interstitium, surrounded by increased amounts of extracellular matrix, and EMMPRIN has been proposed as a contributor factor. The study has evidenced that EMMPRIN displays adverse effects on renal graft survival in terms of the frequent occurrence of DGF, poorer short-term and long-term renal graft function, more profound fibrotic lesions in biopsy specimens, and the degree of proteinuria. This represents an opportunity for more accurate prediction of the post-transplant period and early, non-invasive detection of kidney graft dysfunction. Future studies need to further investigate the clinical significance of the presented results.

Chronic kidney disease (CKD) is associated with renal fibrosis, and develops with the participation of fibroblasts and myofibroblasts from epithelial-to-mesenchymal transition (EMT). In cancer research, the key role of the glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in EMT has been proven. In this study, we evaluate how serum CD147/EMMPRIN affects long-term renal graft function and renal biopsy specimen lesions. In total, 49 renal graft recipients who had a renal biopsy within the last 18 months were retrospectively reviewed. At their most recent appointments, their serum concentrations of CD147/EMMPRIN and renal function were assessed. The occurrence of delayed graft function (DGF), estimated glomerular filtration rate (eGFR) at 1-year post-kidney transplantation (Tx) and the subsequent years of the follow-up period, and renal biopsy specimen lesions, mainly those related to renal fibrosis and tubular atrophy, were also evaluated. Results: CD147/EMMPRIN serum concentration correlated negatively with eGFR at the most recent appointment (ME 69 months) and with eGFR at 1 and 2 years after Tx (p < 0.05, R = −0.69, R = −0.39, and R = −0.40, respectively). CD147/EMMPRIN serum levels correlated positively with urine protein concentrations (p < 0.05, R = 0.73). A positive correlation was further found with the severity of renal biopsy specimen lesions such as interstitial fibrosis (CI), tubular atrophy (CT), double contours of the GBM (CG), mesangial matrix expansion (MM), and arteriolar hyalinosis (AH) (p < 0.05, R = 0.39, R = 0.29, R = 0.41, R = 0.32 and R = 0.40, respectively). Patients with a history of DGF had higher CD147/EMMPRIN serum concentrations (<0.05). Conclusions: CD147/EMMPRIN is linked to poorer long-term renal graft function. Additionally, a high serum concentration of CD147/EMMPRIN affects interstitial fibrosis tubular atrophy (IF/TA) lesions and proteinuria.

• Acute kidney injury
• Chronic allograft nephropathy
• Chronic kidney disease
• Diabetic nephropathy
• Glomerulonephritis
• Glomerulosclerosis
• Hemodialysis
• Matrix metalloproteinases
• Polycystic kidney disease
• Tissue inhibitor of matrix metalloproteinases
• Tubulointerstitial fibrosis

Diabetic nephropathy (DN) is one of the most serious microvascular complications of late-stage diabetes. Glomerular mesangial cell (GMC) proliferation and excessive extracellular matrix (ECM) deposition are the main pathological characteristics associated with the occurrence and development of DN. Yes-associated protein 1 (YAP1) can bind to several transcription factors and is associated with the development of various diseases. However, the effects of YAP1 on DN remain unclear. The aim of the present study was to explore the regulatory effect and potential mechanism of YAP1 in glucose-induced inflammation and ECM deposition in high-glucose-treated GMCs. In the present study, HBZY-1 cell models treated with high glucose were constructed, and the effects of YAP1 on the proliferation, inflammation, ECM deposition and fibrosis of HBZY-1 cells were detected. The results showed that YAP1 was highly expressed in HBZY-1 cells treated with high glucose and that YAP1 silencing decreased cell viability, the levels of inflammatory cytokines, ECM deposition and the degree of fibrosis in cells. Further experiments revealed that NF-κB/Jumonji domain-containing protein D3 (JMJD3) signaling pathway inhibitors alleviated the promoting effect of YAP1 overexpression on inflammatory response and ECM deposition in HBZY-1 cells treated with high glucose. In conclusion, it was demonstrated that YAP1 can promote high glucose-induced inflammation and ECM deposition by activating the NF-κB/JMJD3 signaling pathway in GMCs.

• NF-κB/JMJD3
• YAP1
• diabetic nephropathy
• extracellular matrix deposition
• glomerular mesangial cells
• inflammation

• Hydrogen sulfide
• IRI
• Macrophage polarization
• MicroRNA-21

• Animals
• Cystathionine gamma-Lyase
• Endothelial Cells
• Hydrogen Sulfide
• Inflammation
• Kidney
• Macrophages
• Mice
• Mice, Inbred C57BL
• MicroRNAs/genetics
• Reperfusion Injury

• R01 DK116591 NIDDK NIH HHS
• National Institutes of Health
• American Heart Association

Hypoxia-reperfusion (HR) and inflammation are causes of renal allograft injury. Pathological evidence has indicated that ischemia followed by reperfusion leads to the proteolysis and destruction of the extracellular matrix (ECM) in renal tubular epithelial cells. Matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, play roles in cleaving and reshaping the ECM. Acute accumulation of MMP-9 secreted from neutrophils promotes the incidence of inflammation and exacerbates graft trauma. Our goal was to investigate the activities of MMP-9/MMP-2 and their correlation with HR injury and neutrophil-related inflammation in renal proximal tubular cells.

This model was established by placing HK-2 cells under hypoxic conditions (5% CO₂, 1% O₂) for 6 h and then exposing them to reperfusion (5% CO₂, 21% O₂) for 12 h in a tri-gas incubator. The cell culture medium was collected for culturing polymorphonuclear leukocytes (PMNs). BB-94 (MMP-9 inhibitor) was added to the culture medium in the inhibitor group.

Flow cytometry showed a significant increase in reactive oxygen species (ROS) levels in HK-2 cells from the HR injury group. MMP-9 expression was significantly increased and MMP-2 expression was significantly decreased in HK-2 cells from the HR group. MMP-9 and MPO expression were significantly increased in the HR group, while MPO expression was significantly decreased in the PMN inhibitor group.

The outcomes indicated that MMP-9 and MMP-2 are important components of an underlying pathophysiological mechanism of injury following HR. MMP-9 inhibition may be a potential approach to mitigateHR injury.

• Matrix metalloproteinases
• hypoxia-reperfusion injury
• in vitro model
• inflammation
• ischemia-reperfusion injury
• kidney transplantation

The damage of the endothelial glycocalyx as a consequence of ischemia and/or reperfusion injury (IRI) following kidney transplantation has come at the spotlight of research due to potential associations with delayed graft function, acute rejection as well as long-term allograft dysfunction. The disintegration of the endothelial glycocalyx induced by IRI is the crucial event which exposes the denuded endothelial cells to further inflammatory and oxidative damage. The aim of our review is to present the currently available data regarding complex links between shedding of the glycocalyx components, like syndecan-1, hyaluronan, heparan sulphate, and CD44 with the activation of intricate immune system responses, including toll-like receptors, cytokines and pro-inflammatory transcription factors. Evidence on modes of protection of the endothelial glycocalyx and subsequently maintenance of endothelial permeability as well as novel nephroprotective molecules such as sphingosine-1 phosphate (S1P), are also depicted. Although advances in technology are making the visualization and the analysis of the endothelial glycocalyx possible, currently available evidence is mostly experimental. Ongoing progress in understanding the complex impact of IRI on the endothelial glycocalyx, opens up a new era of research in the field of organ transplantation and clinical studies are of utmost importance for the future.

• endothelial glycocalyx
• immune responses
• inflammation
• ischemia and/or reperfusion injury
• kidney transplantation

• biomarkers
• chronic kidney disease
• interstitial fibrosis

• cell metabolism
• ischaemia reperfusion injury
• machine perfusion
• organ reconditioning
• transplantation

• POI
• Polymorphism
• Primary ovarian insufficiency
• TIMP
• Tissue inhibitor of metalloproteinase

• Adult
• Case-Control Studies
• Female
• Genetic Predisposition to Disease
• Genotype
• Humans
• Polymorphism, Single Nucleotide
• Primary Ovarian Insufficiency/genetics
• Republic of Korea
• Tissue Inhibitor of Metalloproteinase-1/genetics
• Tissue Inhibitor of Metalloproteinase-2/genetics
• Tissue Inhibitor of Metalloproteinase-3/genetics
• Tissue Inhibitor of Metalloproteinases/genetics
• Tissue Inhibitor of Metalloproteinase-4

• IL-8
• MMP-9
• graft
• ischaemia–reperfusion
• kidney

• Calcium-sensing receptor
• Calmodulin
• Diabetes mellitus
• NPS-2143
• P47phox
• R-568
• Renal ischemia/reperfusion injury

• Animals
• Apoptosis
• Diabetes Mellitus, Experimental/pathology
• Epithelial Cells/pathology
• Inflammation
• Kidney/injuries
• Kidney Tubules/pathology
• Lipid Peroxidation
• Oxidation-Reduction
• Rats
• Receptors, Calcium-Sensing/physiology
• Reperfusion Injury/etiology
• Streptozocin

• Acute kidney injury
• Chronic allograft nephropathy
• Chronic kidney disease
• Diabetic nephropathy
• Glomerulosclerosis
• Matrix metalloproteinases
• Polycystic kidney disease
• Tissue inhibitor of metalloproteinase
• Tubulointerstitial fibrosis

• Animals
• Biomarkers, Tumor/metabolism
• Humans
• Kidney Diseases/enzymology
• Kidney Diseases/etiology
• Kidney Diseases/pathology
• Kidney Diseases/therapy
• Matrix Metalloproteinases/metabolism
• Models, Biological
• Tissue Inhibitor of Metalloproteinases/metabolism

Accurate diagnosis of fibrosis is of paramount clinical importance. A human fibrosis classifier based on metzincins and related genes (MARGS) was described previously. In this investigation, expression changes of MARGS genes were explored and evaluated to examine whether the MARGS-based algorithm has any diagnostic value in a rat model of lithium nephropathy. Male Wistar rats (n = 12) were divided into 2 groups (n = 6). One group was given a diet containing lithium (40 mmol/kg food for 7 days, followed by 60mmol/kg food for the rest of the experimental period), while a control group (n = 6) was fed a normal diet. After six months, animals were sacrificed and the renal cortex and medulla of both kidneys removed for analysis. Gene expression changes were analysed using 24 GeneChip^® Affymetrix Rat Exon 1.0 ST arrays. Statistically relevant genes (p-value<0.05, fold change>1.5, t-test) were further examined. Matrix metalloproteinase-2 (MMP2), CD44, and nephroblastoma overexpressed gene (NOV) were overexpressed in the medulla and cortex of lithium-fed rats compared to the control group. TGFβ2 was overrepresented in the cortex of lithium-fed animals 1.5-fold, and 1.3-fold in the medulla of the same animals. In Gene Set Enrichment Analysis (GSEA), both the medulla and cortex of lithium-fed animals showed an enrichment of the MARGS, TGFβ network, and extracellular matrix (ECM) gene sets, while the cortex expression signature was enriched in additional fibrosis-related-genes and the medulla was also enriched in immune response pathways. Importantly, the MARGS-based fibrosis classifier was able to classify all samples correctly. Immunohistochemistry and qPCR confirmed the up-regulation of NOV, CD44, and TGFβ2. The MARGS classifier represents a cross-organ and cross-species classifier of fibrotic conditions and may help to design a test to diagnose and to monitor fibrosis. The results also provide evidence for a common pathway in the pathogenesis of fibrosis.