Summary
Acute kidney injury (AKI) is a highly prevalent, heterogeneous syndrome, associated
with increased short- and long-term mortality. A multitude of different factors cause
AKI including ischemia, sepsis, nephrotoxic drugs, and urinary tract obstruction.
Upon injury, the kidney initiates an intrinsic repair program that can result in adaptive
repair with regeneration of damaged nephrons and functional recovery of epithelial
activity, or maladaptive repair and persistence of damaged epithelial cells with a
characteristic proinflammatory, profibrotic molecular signature. Maladaptive repair
is linked to disease progression from AKI to chronic kidney disease. Despite extensive
efforts, no therapeutic strategies provide consistent benefit to AKI patients. Since
kidney biopsies are rarely performed in the acute injury phase in humans, most of
our understanding of AKI pathophysiology is derived from preclinical AKI models. This
raises the question of how well experimental models of AKI reflect the molecular and
cellular mechanisms underlying human AKI? Here, we provide a brief overview of available
AKI models, discuss their strengths and limitations, and consider important aspects
of the AKI response in mice and humans, with a particular focus on the role of proximal
tubule cells in adaptive and maladaptive repair.
Keywords
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REFERENCES
- International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology.Lancet. 2015; 385: 2616-2643
- Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury.Kidney Int Suppl. 2012; 2: 1-138
- Urine neutrophil gelatinase-associated lipocalin identifies unilateral and bilateral urinary tract obstruction.Nephrol Dial Transplant. 2011; 26: 4132-4135
- Acute kidney injury.Nat Rev Dis Primers. 2021; 7: 52
- Molecular nephrology: types of acute tubular injury.Nat Rev Nephrol. 2019; 15: 599-612
- Recommendations on acute kidney injury biomarkers from the Acute Disease Quality Initiative Consensus Conference: a consensus statement.JAMA Netw Open. 2020; 3e2019209
- Subclinical AKI: ready for primetime in clinical practice?.J Nephrol. 2019; 32: 9-16
- Acute kidney injury.Lancet. 2019; 394: 1949-1964
- Unique transcriptional programs identify subtypes of AKI.J Am Soc Nephrol. 2017; 28: 1729-1740
- Rationale and design of the Kidney Precision Medicine Project.Kidney Int. 2021; 99: 498-510
- Bridging translation for acute kidney injury with better preclinical modeling of human disease.Am J Physiol Renal Physiol. 2016; 310: F972-F984
- Bridging translation by improving preclinical study design in AKI.J Am Soc Nephrol. 2015; 26: 2905-2916
- Development of newly formed nephrons in the goldfish kidney following hexachlorobutadiene-induced nephrotoxicity.Toxicol Pathol. 1990; 18: 32-38
- Experimental models of acute kidney injury for translational research.Nat Rev Nephrol. 2022; 18: 277-293
- A fish model of renal regeneration and development.ILAR J. 2001; 42: 285-291
- New tides: using zebrafish to study renal regeneration.Transl Res. 2014; 163: 109-122
- Kidney development and disease in the zebrafish.J Am Soc Nephrol. 2005; 16: 299-304
- Histone deacetylase inhibitor enhances recovery after AKI.J Am Soc Nephrol. 2013; 24: 943-953
- Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury.J Biol Chem. 1998; 273: 4135-4142
- Mammalian target of rapamycin mediates kidney injury molecule 1-dependent tubule injury in a surrogate model.J Am Soc Nephrol. 2016; 27: 1943-1957
- Identification of adult nephron progenitors capable of kidney regeneration in zebrafish.Nature. 2011; 470: 95-100
- Inhibition of histone deacetylase expands the renal progenitor cell population.J Am Soc Nephrol. 2010; 21: 794-802
- 16 - urinary system.in: Treuting PM Dintzis SM Montine KS Comparative Anatomy and Histology. 2nd ed. Academic Press, 2018: 275-301
- Animal models of renal dysfunction: acute kidney injury.Expert Opin Drug Discov. 2009; 4: 629-641
- A genetic model for in vivo proximity labelling of the mammalian secretome.Open Biol. 2022; 12220149
- Cell-specific translational profiling in acute kidney injury.J Clin Invest. 2014; 124: 1242-1254
- TNF-α mediates increased susceptibility to ischemic AKI in diabetes.Am J Physiol Renal Physiol. 2013; 304: F515-F521
- Severe renal mass reduction impairs recovery and promotes fibrosis after AKI.J Am Soc Nephrol. 2014; 25: 1496-1507
- Chapter 3 - the human kidney: parallels in structure, spatial development, and timing of nephrogenesis.in: Little MH Kidney Development, Disease, Repair and Regeneration. Academic Press, 2016: 27-40
- Large animal models for translational research in acute kidney injury.Ren Fail. 2020; 42: 1042-1058
- Of mice and not men: differences between mouse and human immunology.J Immunol. 2004; 172: 2731-2738
- Modeling oxidative injury response in human kidney organoids.Stem Cell Res Ther. 2022; 13: 76
- Evaluation of cisplatin-induced injury in human kidney organoids.Am J Physiol Renal Physiol. 2020; 318: F971-F978
- Human pluripotent stem cell-derived kidney organoids with improved collecting duct maturation and injury modeling.Cell Rep. 2020; 33108514
- Nephron organoids derived from human pluripotent stem cells model kidney development and injury.Nat Biotechnol. 2015; 33: 1193-1200
- Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.Nature. 2015; 526: 564-568
- Bioprinted pluripotent stem cell-derived kidney organoids provide opportunities for high content screening.bioRxiv. 2018; (Published online December 23, 2018)https://doi.org/10.1101/505396
- High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping.Cell Stem Cell. 2018; 22 (e4): 929-940
- Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair.Sci Transl Med. 2022; 14: eabj4772
- SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids.Cell Stem Cell. 2022; 29 (e8): 217-231
- Interleukin-1β activates a MYC-dependent metabolic switch in kidney stromal cells necessary for progressive tubulointerstitial fibrosis.J Am Soc Nephrol. 2018; 29: 1690-1705
- Regrow or repair: an update on potential regenerative therapies for the kidney.J Am Soc Nephrol. 2022; 33: 15-32
- Kidney repair and regeneration: perspectives of the NIDDK (Re)Building a Kidney consortium.Kidney Int. 2022; 101: 845-853
- A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery.Cell Stem Cell. 2022; 29 (e7): 1083-1101
- Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation.Nat Mater. 2021; 20: 260-271
- Human iPSC-derived renal organoids engineered to report oxidative stress can predict drug-induced toxicity.iScience. 2022; 25103884
- Phase II trials in drug development and adaptive trial design.JACC Basic Transl Sci. 2019; 4: 428-437
- Acute kidney injury and maladaptive tubular repair leading to renal fibrosis.Curr Opin Nephrol Hypertens. 2020; 29: 310-318
- Mitochondrial quality control in kidney injury and repair.Nat Rev Nephrol. 2020; 17: 299-318
- Autophagy in kidney homeostasis and disease.Nat Rev Nephrol. 2020; 16: 489-508
- Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection.Nat Rev Nephrol. 2021; 17: 335-349
- Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2: 94716
- Transcriptional trajectories of human kidney injury progression.JCI Insight. 2018; 3123151
- Cellular plasticity in kidney injury and repair.Nat Rev Nephrol. 2017; 13: 39-46
- How much can the tubule regenerate and who does it? An open question.Nephrol Dial Transplant. 2016; 31: 1243-1250
- Isolation of renal progenitor cells from adult human kidney.Am J Pathol. 2005; 166: 545-555
- Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys.J Am Soc Nephrol. 2006; 17: 2443-2456
- Isolation and characterization of progenitor-like cells from human renal proximal tubules.Am J Pathol. 2011; 178: 828-837
- Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury.Stem Cells. 2012; 30: 1714-1725
- Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration.J Pathol. 2013; 229: 645-659
- Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury.Nat Commun. 2018; 9: 1344
- Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury.Proc Natl Acad Sci U S A. 2021; 118e2026684118
- Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury.Proc Natl Acad Sci U S A. 2020; 117: 15874-15883
- In vivo clonal analysis reveals lineage-restricted progenitor characteristics in mammalian kidney development, maintenance and regeneration.Cell Rep. 2014; 7: 1270-1283
- Differentiated kidney epithelial cells repair injured proximal tubule.Proc Natl Acad Sci U S A. 2014; 111: 1527-1532
- Repair of injured proximal tubule does not involve specialized progenitors.Proc Natl Acad Sci U S A. 2011; 108: 9226-9231
- FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury.J Clin Invest. 2019; 129: 5501-5517
- Intrinsic epithelial cells repair the kidney after injury.Cell Stem Cell. 2008; 2: 284-291
- Origin of regenerating tubular cells after acute kidney injury.Proc Natl Acad Sci U S A. 2014; 111: 1533-1538
- Mitochondrial biogenesis in the acutely injured kidney.Nephron Clin Pract. 2014; 127: 42-45
- Defective fatty acid oxidation in renal tubular epithelial cells plays a key role in kidney fibrosis development.Nat Med. 2015; 21: 37-46
- Alteration of fatty acid oxidation in tubular epithelial cells: from acute kidney injury to renal fibrogenesis.Front Med (Lausanne). 2015; 2: 52
- Single cell profiling in COVID-19 associated acute kidney injury reveals patterns of tubule injury and repair in human.bioRxiv. 2021; (Published online October 6, 2021)https://doi.org/10.1101/2021.10.05.463150
- Mitochondrial pathology and glycolytic shift during proximal tubule atrophy after ischemic AKI.J Am Soc Nephrol. 2016; 27: 3356-3367
- Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality.Nat Metab. 2020; 2: 732-743
- Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice.Nat Commun. 2017; 8: 14181
- Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy.J Am Soc Nephrol. 2014; 25: 2526-2538
- PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice.J Clin Invest. 2011; 121: 4003-4014
- PGC1α-dependent NAD biosynthesis links oxidative metabolism to renal protection.Nature. 2016; 531: 528-532
- Differential role of nicotinamide adenine dinucleotide deficiency in acute and chronic kidney disease.Nephrol Dial Transplant. 2021; 36: 60-68
- De novo NAD+ biosynthetic impairment in acute kidney injury in humans.Nat Med. 2018; 24: 1351-1359
- Renal gluconeogenesis: its importance in human glucose homeostasis.Diabetes Care. 2001; 24: 382-391
- Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis.Kidney Int. 2012; 81: 442-448
- Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD.Nat Rev Nephrol. 2015; 11: 264-276
- Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair.Elife. 2021; 10: e68603
- Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis.Kidney Int. 2012; 82: 172-183
- Cellular senescence and senotherapies in the kidney: current evidence and future directions.Front Pharmacol. 2020; 11: 755
- Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.Nat Med. 2010; 16: 143-535
- Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation.Aging Cell. 2008; 7: 491-497
- Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair.Sci Transl Med. 2021; 13: eabb0203
- Cyclin G1 and TASCC regulate kidney epithelial cell G2-M arrest and fibrotic maladaptive repair.Sci Transl Med. 2019; 11: eaav4754
- Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease.EBioMedicine. 2019; 47: 446-456
- Mapping the human kidney using single-cell genomics.Nat Rev Nephrol. 2022; 18: 347-360
- Multi-omic approaches to acute kidney injury and repair.Curr Opin Biomed Eng. 2021; 20100344
- Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration.Nat Commun. 2022; 13: 4018
- An atlas of healthy and injured cell states and niches in the human kidney.bioRxiv. 2021; (Published online July 7, 2021)https://doi.org/10.1101/2021.07.28.454201
- Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury.Genome Med. 2022; 14: 103
- Urinary single-cell sequencing captures kidney injury and repair processes in human acute kidney injury.Kidney International. 2022; (Published online November 15, 2022)https://doi.org/10.1016/j.kint.2022.07.032
Article info
Publication history
Published online: January 04, 2023
Footnotes
Financial support: Supported by the German Research Foundation postdoctoral scholarship GE 3179/ 1-1 (L.M.S.G.), and the work in Andrew P. McMahon's laboratory is supported by grants from the National Institutes of Health (UC2 DK126024-01, R01 DK054364, R01 DK121409, and R01 DK126925-01) to Andrew P. McMahon.
Conflict of interest statement: Andrew P. McMahon serves as a scientific advisor to Novartis, TRESTLE Biotherapeutics, eGENESIS, and IVIVA Medical. The remaining author reports no conflict of interest.
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