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AKI: an increasingly recognized risk factor for CKD development and progression

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Abstract

Acute kidney injury (AKI) is an increasing health burden with high morbidity and mortality rates worldwide. AKI is a risk factor for chronic kidney disease (CKD) development and progression to end stage renal disease (ESRD). Rapid action is required to find treatment options for AKI, plus to anticipate the development of CKD and other complications. Therefore, it is essential to understand the pathophysiology of AKI to CKD transition. Over the last several years, research has revealed maladaptive repair to be an interplay of cell death, endothelial dysfunction, tubular epithelial cell senescence, inflammatory processes and more—terminating in fibrosis. Various pathological mechanisms have been discovered and reveal targets for potential interventions. Furthermore, there have been clinical efforts measures for AKI prevention and progression including the development of novel biomarkers and prediction models. In this review, we provide an overview of pathophysiological mechanisms involved in kidney fibrosis. Furthermore, we discuss research gaps and promising therapeutic approaches for AKI to CKD progression.

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Abbreviations

ADQI:

Acute disease quality initiative

Ag-presentation:

Antigen presentation

AKD:

Acute kidney disease

AKI:

Acute kidney injury

Akt:

Protein kinase B, PKB

Alpha-SMA:

α-Smooth muscle actin

AQP2:

Aquaporine 2

ASC:

Adipose mesenchymal stem cells

ATN:

Acute tubular necrosis

BC-SC:

Blood cord stem cells

bFGF:

Basic fibroblast growth factor

BM:

Bone marrow

BUN:

Blood urea nitrogen

CCL2:

CC-chemokine ligand 2

CCR2:

C–C chemokine receptor type 2

CDDO-dhTFEA:

CDDO-9,11-dihydro-trifluoroethyl Amide

CDDO-Im:

CDDO-imidazole

CDDO-Me:

CDDO-methyl ester

CI:

Confidence interval

CKD:

Chronic kidney disease

CRAC channel:

Ca2+ release-activated Ca2+ channel

CRRT:

Continuous renal replacement therapy

CTGF:

CCN2 or connective tissue growth factor

Cxcl12:

CXC-Motif-Chemokin 12

CVD:

Cardiovascular diseases

DAMPs:

Damaged-associated molecular patterns

DCs:

Dendritic cells

DGF:

Delayed graft function

DM:

Diabetes mellitus

DN:

αβTCR double negative T cells

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EMP:

Epithelial-mesenchymal plasticity

EMT:

Epithelial-mesenchymal transition

EndMT:

Endothelial-to-mesenchymal transition

EPC:

Endothelial progenitor cells

ER:

Endoplasmic reticulum

ERK 1/2:

Extracellular-signal-regulated kinase 1/2

ESRD:

End stage renal disease

EVs:

Extracellular vesicles

FGF-2:

Fibroblast growth factor

GFR:

Glomerular filtration rate

Glom:

Glomerular

HGF:

Hepatocyte growth factor

HPSE:

Heparanase

HR:

Hazard ratio

HSC:

Hematopoietic SC

IFN-γ:

Interferon γ

IGF1:

Insulin-like growth factor 1

IGFBP7:

Insulin-like growth factor-binding protein 7

IL:

Interleukin

iPS:

Induced pluripotent SC

IRI:

Ischemic reperfusion injury

ISN:

International Society of Nephrology

KC:

Keratinocyte-derived chemokine

KDIGO:

Kidney disease improving global outcomes

Keap1:

Kelch-like ECH-associated protein 1

KIM-1:

Kidney injury molecule-1

KO:

Knock out

LSC:

Liver stem cells

M2:

M2 macrophages

MCP-1:

Monocyte chemoattractant protein-1

MHC:

Major histocompatibility complex

MLKL:

Mixed lineage kinase domain-like protein

MMP:

Matrix metalloprotease

MSC:

Mesenchymal stem cells

NET:

Neutrophil extracellular traps

NF-κB:

Nuclear factor 'kappa-light-chain-enhancer' of activated B-cells

NGAL:

Neutrophil gelatinase-associated lipocalin

NK cells:

Natural killer cells

NO:

Nitric oxide

Nrf2:

Nuclear factor erythroid 2-related factor 2

Orai1:

Calcium release-activated calcium channel protein 1

PDGF:

Platelet-derived growth factor

PIIINP:

Procollagen type III N-terminal peptide

PTEN:

Phosphatase and Tensin homolog

RANTES:

Regulated upon activation, normal T-cell expressed and secreted

RIPK1:

Receptor-interacting protein kinase-1

SC:

Stem cells

Snai1:

Snail Family Transcriptional Repressor 1

T2DM:

Type 2 diabetes mellitus

TEC:

Tubular epithelial cells

TGF-β:

Transforming growth factor β

Th cells:

T helper cells,

Th1:

T helper cell 1

Th2:

T helper cell 2

Th17:

T helper cell 17

TIMP-2:

Tissue inhibitor of metalloproteinases-2

TNF:

Tumor necrosis factor

TRADD:

TNF-receptor dead domain

Treg:

Regulatory T cells

Twist1:

Twist Family BHLH Transcription Factor 1

UUO:

Unilateral ureter obstruction

VEGF:

Vascular endothelial growth factor

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Funding

This study was (partially) funded by the Italian Ministry of Education, University and Research (MIUR) program “Departments of Excellence 2018-2022”, AGING Project—Department of Translational Medicine, Università del Piemonte Orientale (UPO). HR was supported by grants from the NIDDK and philanthropic gifts from Rogelio Miro and Sammy Eldin. JTK was supported with a scholarship by the Dr. Werner Jackstädt-Foundation (project number S 134–10.117).

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Authors and Affiliations

  1. Division of Nephrology, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Ross 965, 720 Rutland Ave, Baltimore, MD, 21206, USA

    J. T. Kurzhagen & H. Rabb

  2. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    S. Dellepiane

  3. Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), “Maggiore Della Carità” University Hospital, Novara, Italy

    V. Cantaluppi

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  1. J. T. Kurzhagen
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Correspondence to H. Rabb.

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V. Cantaluppi: On behalf of the AKI and CRRT Project Group of the Italian Society of Nephrology (SIN).

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Kurzhagen, J.T., Dellepiane, S., Cantaluppi, V. et al. AKI: an increasingly recognized risk factor for CKD development and progression. J Nephrol 33, 1171–1187 (2020). https://doi.org/10.1007/s40620-020-00793-2

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