Acute kidney injury (AKI) causes damage to the renal epithelium, initiating a reparative process intended to restore renal function. Although effective repair can result in the complete recovery of kidney function, this process is frequently incomplete. In instances where repair is unsuccessful, the kidney experiences maladaptive alterations that may progressively result in chronic kidney disease (CKD), a phenomenon referred to as failed repair. This condition is precipitated by hypotensive, septic, or toxic insults, which initiate a series of pathophysiological processes, including microcirculatory dysfunction, the activation of inflammatory responses, and the death of tubular epithelial cells. These events collectively compromise renal function and trigger a complex repair response. This review provides a comprehensive examination of the multifactorial mechanisms underlying the initiation and progression of AKI, the regenerative pathways facilitating structural recovery in severely damaged kidneys, and the critical transition from adaptive repair to maladaptive remodeling. Central to this transition are mechanisms such as epigenetic reprogramming, G2/M cell-cycle arrest, cellular senescence, mitochondrial dysfunction, metabolism reprogramming, and cell death, which collectively drive the progression of CKD. These mechanistic insights offer a robust foundation for the development of targeted therapeutic strategies aimed at enhancing adaptive renal repair.

Kidney ischemia-reperfusion (I/R) injury is an acute clinical condition associated with inflammation and tissue damage during and after ischemia and reperfusion periods. In I/R injury, macrophages contribute to injury, and a family of proteins called toll-like receptors seem to have an immune modulatory role. When activated, TLRs initiate a series of signaling pathways, including MyD88 and TRIF. These pathways regulate the activation of tissue macrophages into either 'classically activated' M1 or 'alternatively activated' M2 phenotypes. Indeed, the relative abundance of these macrophage phenotypes defines the tissue injury level, which consequently requires reparative processes. The initial effector pro-inflammatory M1 macrophages aggravate tissue injury. Conversely, tissue reparative and anti-inflammatory M2 macrophages promote tissue repair and resolution-increased TLR signalling results in increased inflammation, prolonged healing and even renal failure. New evidence indicates that the change of macrophage responses through pharmacological targeting of the TLR pathways that regulate inflammation and tissue repair may have therapeutic implications. Some experimental treatment methods, in which early phases have been elaborated through experimental animal models, are TLR antagonists, small molecule inhibitors and nanotechnology-based delivery systems for Antisense oligonucleotide. Nevertheless, because the pathways regulated by TLRs and the subsets of macrophages are so countless and entangled, more extensive study is needed to provide more targeted actions. These findings shed light on the role and regulation of TLRs in macrophages during kidney I/R injury and investigate potential treatments with the potential to enhance care in this highly damaging condition.

Variable flip angle (VFA) and modified Look-Locker inversion recovery (MOLLI) are frequently used for noninvasive evaluation of renal interstitial fibrosis (IF) in chronic kidney disease (CKD). However, controversy remains over which method is preferred.

To compare the diagnostic efficacy of VFA and MOLLI for T1 mapping in evaluating renal IF.

Prospective.

Fifty-one participants with CKD (CKD stage 1-5, 35 males) and 18 healthy volunteers (eight males).

3.0 T, three-dimensional gradient echo sequence for B1+ VFA, and two-dimensional gradient echo sequence for MOLLI.

Image quality was assessed on a five-point scale. Cortex and medulla T1 values (cT1 and mT1), corticomedullary T1 value difference (ΔT1, medulla - cortex), and corticomedullary T1 value ratio (ratio T1, cortex:medulla) were compared between VFA and MOLLI as well as between IF grade (0-4) based on biopsy.

Intraclass correlation coefficient, Bland-Altman analysis, analysis of variance, Kruskal-Wallis test, correlation analysis, and receiver operating characteristics analysis with the area under the curve (AUC). P-value <0.05 was considered significant.

MOLLI provided significantly better image quality compared to VFA. cT1 and mT1 values significantly differed between VFA and MOLLI (cT1-VFA: 1771.4 ± 139.4 msec vs. cT1-MOLLI: 1729.9 ± 132.1 msec; mT1-VFA: 2076.0 [interquartile range (IQR): 2045.9-2129.9] msec vs. mT1-MOLLI: 2039.2 [IQR: 1997.8-2071.6] msec). ΔT1 and ratio T1 values were not different between VFA and MOLLI (ΔT1: 300.8 ± 71.4 vs. 306.0 ± 78.4, respectively, P = 0.33 and ratio T1: 0.85 ± 0.038 vs. 0.85 ± 0.041, respectively, P = 0.064). No difference was observed between T1 variables and T1 mapping methods in diagnosing IF.

ΔT1 and ratio T1 were not different between VFA and MOLLI. Both VFA and MOLLI are effective for noninvasive assessment of renal IF.

2 TECHNICAL EFFICACY: Stage 2.

Renal ischemia-reperfusion injury (RIRI) is a major cause of acute kidney injury (AKI). Autophagy is an important mechanisms involved in this damage. In this study, we investigated effect of selenium on autophagy in kidney following IRI.

In this study, 24 Wistar male rats (200 ± 20 gr) were divided into 4 groups: 1) Sham 2) Sham+ Sodium selenite (0.5 mg/kg) 3) Ischemia-reperfusion (I/R) 4) I/R + sodium selenite. RIRI induces by vascular microclamp for 45 min. At the end of study, blood was taken from the heart tissue and used to measure BUN and Creatinine with the kit, the left kidney tissue was frozen for measurement of LC3II, LC3I, Beclin1, Rab11a, P62, and Caspase3 by western blot technique and measurement of mir21a by RT-PCR method. In addition, right kidney tissue was placed in formalin for histological studies with Haematoxylin‎‎-eosin staining.

According to the results, in the I/R group compared to the sham group, serum levels of creatinine and urea, amount of autophagy including expression levels of Lc3II/Lc3I, beclin1, Rab11a, Cleaved Caspase3/Pro Caspase3 proteins significantly increased and expression of p62 decreased. Also, mir21a gene expression significantly decreased in the I/R group. According to histological results, ischemia-reperfusion has caused kidney tissue damage, such as destruction of the brush border of renal tubules, congestion, and leukocyte filtration. Our results showed that pretreatment with selenium reduced tissue damage and moderated the expression changes of the mentioned proteins.

It seems selenium inhibits autophagy by changing the expression levels of mediator molecules Rab11a and mir21a, and it can apply its healing effects in the damage caused by ischemia and reperfusion of kidney tissue in an animal model.

We evaluate the association of early postoperative urinary c-c motif chemokine ligand 14 (CCL14) and persistent severe acute kidney injury (AKI) in pediatric post-cardiac surgery patients.

This is a retrospective single-center cohort study of patients < 18 years of age undergoing cardiac surgery who provided a biorepository urine sample within the first 24 postoperative hours. Persistent severe AKI was defined as any AKI stage lasting for ≥ 72 h with at least one time point of AKI stage 2 or 3 during that time frame. Patients with persistent severe AKI were matched 2:1 with non-AKI patients on age and sex. Urine samples were measured for CCL14 concentration. Logistic regression was used to evaluate associations between CCL14 and persistent severe AKI.

Persistent severe AKI occurred in 14 (5.4%) patients and was more common in patients with higher surgical complexity and longer cardiopulmonary bypass and cross-clamp duration. Patients with persistent severe AKI had longer median cardiac intensive care unit (CICU) (5 [3, 10] vs. 2 [1.5, 5.5], p-value = 0.039) and hospital length of stays (13.5 [7.8, 16.8] vs. 6 [4,8], p-value = 0.009). There was no difference in CCL14 levels between patients with and without persistent severe AKI (46.7 pg/ml [31.0, 82.9] vs. 44.2 pg/ml [25.1, 74.9], p-value = 0.49) in univariable and logistic regression.

In this heterogenous cohort of children undergoing cardiac surgery, CCL14 was not associated with persistent severe AKI. Future studies are needed to evaluate the use of CCL14 for predicting persistent severe AKI in children.

Acute kidney injury (AKI) involves a series of syndromes characterized by a rapid increase in creatinine levels. Ferroptosis, as an iron-dependent mode of programmed cell death, reportedly participates in the pathogenesis of AKI. Methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification has been recently associated with various kidney diseases; however, the mechanism of METTL3 crosstalk with the molecules involved in ferroptosis is not clearly understood. Here, we investigated the crosstalk between METTL3-mediated m6A modification and ferroptosis in AKI. METTL3-mediated m6A modification was elevated in patients with AKI, folic acid-AKI mice, and tert-butyl hydrogen peroxide-stimulated TCMK-1 cells. Inhibition of METTL3 expression in vivo and in vitro alleviated the damage and ferroptosis in renal tubular cells. Methylated RNA immunoprecipitation sequencing showed that heme oxygenase 1 (Hmox1/HO-1) was the METTL3 target. RNA immunoprecipitation-qPCR indicated that anti-insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) could be used as a reader to bind to the methylated site of Hmox1 mRNA to maintain its stability. Hmox1 knockdown in vitro reduced the accumulation of iron ions and alleviated ferroptosis. METTL3 mediates the m6A modification of Hmox1 mRNA and maintains its stability in an IGF2BP3-dependent manner, which causes iron overload in renal tubular epithelial cells, leading to ferroptosis and AKI.

There has been growing interest in using quantitative magnetic resonance imaging (MRI) to describe and understand the pathophysiology of acute kidney injury (AKI). The ability to assess kidney blood flow, perfusion, oxygenation, and changes in tissue microstructure at repeated timepoints is hugely appealing, as this offers new possibilities to describe nature and severity of AKI, track the time-course to recovery or progression to chronic kidney disease (CKD), and may ultimately provide a method to noninvasively assess response to new therapies. This could have significant clinical implications considering that AKI is common (affecting more than 13 million people globally every year), harmful (associated with short and long-term morbidity and mortality), and currently lacks specific treatments. However, this is also a challenging area to study. After the kidney has been affected by an initial insult that leads to AKI, complex coexisting processes ensue, which may recover or can progress to CKD. There are various preclinical models of AKI (from which most of our current understanding derives), and these differ from each other but more importantly from clinical AKI. These aspects are fundamental to interpreting the results of the different AKI studies in which renal MRI has been used, which encompass different settings of AKI and a variety of MRI measures acquired at different timepoints. This review aims to provide a comprehensive description and interpretation of current studies (both preclinical and clinical) in which MRI has been used to assess AKI, and discuss future directions in the field. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Acute kidney injury (AKI) is a common clinical syndrome with few effective treatments. Though the kidney can regenerate after injury, the molecular mechanisms regulating this process remain poorly understood. Pax2 and Pax8 are DNA-binding transcription factors that are upregulated after kidney injury. However, their function during the response to AKI remains incompletely defined. In this report, we develop a model of ischemic AKI in female mice with mosaic nephrons comprised of both Pax2 and Pax8 mutant and wild-type proximal tubule cells with fixed lineages. Each population therefore experiences identical physiological and injury conditions in the same animal. In these female mice, we show that before injury the S1 and S2 segments of the proximal tubule are depleted of Pax-mutant cells, whereas mutant cells are preserved in the S3 segment. Retained S3 Pax-mutant cells develop a preconditioned phenotype that overlaps with gene expression signatures in AKI. In response to ischemic AKI, which most strongly damages the S3 proximal tubule, injury-resistant mutant S3 cells are more likely to proliferate. Pax-mutant cells then preferentially repopulate the S3 segment of the proximal tubule. Our results indicate that Pax2 and Pax8 are not required for regeneration of the S3 proximal tubule after ischemic AKI. Together, our findings indicate that Pax proteins play a critical role in determining the segment-specific proximal tubule gene expression patterns that dictate vulnerability to ischemic injury.NEW & NOTEWORTHY Acute kidney injury (AKI) is a common clinical syndrome with few effective treatments. In this report, we identify a novel and proximal tubule segment-specific role for the Pax family of transcription factors in the differential sensitivity of proximal tubule segments to ischemic AKI. These results may lead to new therapeutic targets for the prevention and treatment of AKI.

Acute kidney injury (AKI) is a common complication during hospitalization and is associated with adverse outcomes.

To evaluate whether diagnostic and therapeutic recommendations sent by a kidney action team through the electronic health record improve outcomes among patients hospitalized with AKI compared with usual care.

Randomized clinical trial conducted at 7 hospitals in 2 health systems: in New Haven, Bridgeport, New London, and Waterbury, Connecticut, and Westerly, Rhode Island; and in Baltimore, Maryland. Hospitalized patients with AKI were randomized between October 29, 2021, and February 8, 2024. Final follow-up occurred February 22, 2024.

An alert about AKI was sent to the kidney action team, consisting of a study physician and study pharmacist, which sent personalized recommendations through the electronic health record in 5 major categories (diagnostic testing, volume, potassium, acid base, and medications) within 1 hour of AKI detection. The note was immediately visible to anyone with access to the electronic health record. Randomization to the intervention or usual care occurred after the recommendations were generated, but the note was only delivered to clinicians of patients randomized to the intervention group.

The primary outcome was a composite outcome consisting of AKI progression to a higher stage of AKI, dialysis, or mortality occurring while the patient remained hospitalized and within 14 days from randomization.

Of the 4003 patients randomized (median age, 72 years [IQR, 61-81 years), 1874 (47%) were female and 931 (23%) were Black patients. The kidney action team made 14 539 recommendations, with a median of 3 (IQR, 2-5) per patient. The primary outcome occurred in 19.8% of the intervention group and in 18.4% in the usual care group (difference, 1.4%, 95% CI, -1.1% to 3.8,% P = .28). Of 6 secondary outcomes, only 1 secondary outcome, rates of recommendation implementation, significantly differed between the 2 groups: 2459 of 7270 recommendations (33.8%) were implemented in the intervention group and 1766 of 7269 undelivered recommendations (24.3%) were implemented in the usual care group within 24 hours (difference, 9.5%; 95% CI, 8.1% to 11.0%).

Among patients hospitalized with AKI, recommendations from a kidney action team did not significantly reduce the composite outcome of worsening AKI stage, dialysis, or mortality, despite a higher rate of recommendation implementation in the intervention group than in the usual care group.

ClinicalTrials.gov Identifier: NCT04040296.

JNK-associated leucine zipper protein (JLP) is a newly identified renal endogenous anti-fibrotic factor that is selectively enriched in renal tubular epithelial cells (TECs). The loss of JLP by TECs is a landmark event that heralds the progression of kidney fibrosis. JLP deficiency ensues a series of pathogenetic cellular processes that are conducive to fibrotic injury. Inflammatory injury is functionally relevant in fibrotic kidneys, and TECs play an essential role in fueling inflammation through aberrant secretions. It is speculated that the loss of JLP in TECs is associated with the relentless inflammation during the development of kidney fibrosis. This study examined the alteration of a panel of inflammatory signatures in TECs under kidney fibrotic circumstances using a Jlp gene-modified unilateral ureteral obstruction (UUO) mouse model or cultured HK-2 cells. It was found that a deficiency of JLP in TECs led to a significant increase in the secretion of inflammatory cytokines including interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and monocyte chemotactic protein-1 (MCP-1), overactivation of the nuclear factor (NF)-κB/c-Jun N-terminal kinase (JNK) pathway, as well as nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis in response to pro-fibrotic damage. Additionally, the absence of JLP resulted in enhanced macrophage migration and fibroblast activation as paracrine effects elicited by injured TECs. In conclusion, the loss of JLP in TECs catalyses inflammatory injuries in the development of kidney fibrosis.

Acute kidney injury (AKI) is a common condition associated with significant morbidity, mortality, and cost. Injured kidney tissue can regenerate after many forms of AKI. However, there are no treatments in routine clinical practice to encourage recovery. In part, this shortcoming is due to an incomplete understanding of the genetic mechanisms that orchestrate kidney recovery. The advent of high-throughput sequencing technologies and genetic mouse models has opened an unprecedented window into the transcriptional dynamics that accompany both successful and maladaptive repair. AKI recovery shares similar cell-state transformations with kidney development, which can suggest common mechanisms of gene regulation. Several powerful bioinformatic strategies have been developed to infer the activity of gene regulatory networks by combining multiple forms of sequencing data at single-cell resolution. These studies highlight not only shared stress responses but also key changes in gene regulatory networks controlling metabolism. Furthermore, chromatin immunoprecipitation studies in injured kidneys have revealed dynamic epigenetic modifications at enhancer elements near target genes. This review will highlight how these studies have enhanced our understanding of gene regulation in injury response and regeneration.

Acute kidney injury (AKI) is characterized by an abrupt decline of excretory kidney function. The incidence of AKI has increased in the past decades. Patients diagnosed with AKI often undergo diverse clinical trajectories, such as early or late recovery, relapses, and even a potential transition from AKI to chronic kidney disease (CKD). Although recent clinical studies have demonstrated a strong association between AKI and progression of CKD, our understanding of the complex relationship between AKI and CKD is still evolving. No cohort study has succeeded in painting a comprehensive picture of these multi-faceted pathways. To address this lack of understanding, the idea of acute kidney disease (AKD) has recently been proposed. This presents a new perspective to pinpoint a period of heightened vulnerability following AKI, during which a patient could witness a substantial decline in glomerular filtration rate, ultimately leading to CKD transition. Although AKI is included in a range of kidney conditions collectively known as AKD, spanning from mild and self-limiting to severe and persistent, AKD can also occur without a rapid onset usually seen in AKI, such as when kidney dysfunction slowly evolves. In the present review, we summarize the most recent findings about AKD, explore the current state of biomarker discovery related to AKD, discuss the latest insights into pathophysiological underpinnings of AKI to CKD transition, and reflect on therapeutic challenges and opportunities that lie ahead.

To investigate the potential of Native T1-mapping in predicting the prognosis of patients with chronic kidney disease (CKD).

We enrolled 119 CKD patients as the study subjects and included 20 healthy volunteers as the control group, with follow-up extending until October 2022. Out of these patients, 63 underwent kidney biopsy measurements, and these patients were categorized into high (25-50%), low (< 25%), and no renal interstitial fibrosis (IF) (0%) groups. The study's endpoint event was the initiation of renal replacement therapy, kidney transplantation, or an increase of over 30% in serum creatinine levels. Cox regression analysis determined factors influencing unfavorable kidney outcomes. We employed Kaplan-Meier analysis to contrast kidney survival rates between the high and low T1 groups. Additionally, receiver-operating characteristic (ROC) curve analysis assessed the predictive accuracy of Native T1-mapping for kidney endpoint events.

T1 values across varying fibrosis degree groups showed statistical significance (F = 4.772, P < 0.05). Multivariate Cox regression pinpointed 24-h urine protein, cystatin C(CysC), hemoglobin(Hb), and T1 as factors tied to the emergence of kidney endpoint events. Kaplan-Meier survival analysis revealed a markedly higher likelihood of kidney endpoint events in the high T1 group compared to the low T1 value group (P < 0.001). The ROC curves for variables (CysC, T1, Hb) tied to kidney endpoint events demonstrated area under the curves(AUCs) of 0.83 (95%CI: 0.75-0.91) for CysC, 0.77 (95%CI: 0.68-0.86) for T1, and 0.73 (95%CI: 0.63-0.83) for Hb. Combining these variables elevated the AUC to 0.88 (95%CI: 0.81-0.94).

Native T1-mapping holds promise in facilitating more precise and earlier detection of CKD patients most at risk for end-stage renal disease.

The aim of the present study was to establish a reference interval (RI) for urine kidney injury molecule-1 (KIM-1) in healthy cats.

History, physical examination, blood pressure, and feline immunodeficiency virus and feline leukemia virus serology status were determined. A complete blood cell count, serum biochemical profile, urinalysis and kidney ultrasound were performed, and N-terminal pro-brain natriuretic peptide, total thyroxine (TT4) and urine KIM-1 were measured. An RI was calculated and the effect of age, sex, body condition score (BCS), blood pressure, symmetric dimethylarginine (SDMA), serum creatinine concentration (SCr), phosphorus, TT4, urine specific gravity (USG) and mid-sagittal kidney length on urine KIM-1 was evaluated using a general linear model.

Of 69 recruited cats, 50 met the inclusion criteria. There were 35 male cats and 15 female cats, with a median age of 4.3 years (range 1.0-12.3), median weight of 5.11 kg (range 2.52-8.45) and median BCS of 6/9 (range 3-8). The median serum concentrations were SDMA 11.0 µg/dl (range 2-14), SCr 88.5 µmol/l (range 47-136), phosphorus 1.41 mmol/l (range 0.8-2.2) and TT4 32.0 nmol/l (range 17-51). Median USG was 1.057 (range 1.035-1.076), mid-sagittal left kidney length was 3.50 cm (range 2.94-4.45) and mid-sagittal right kidney length was 3.70 cm (range 3.06-4.55). The derived RI for urine KIM-1 was 0.02-0.68. USG was a significant (P <0.001) predictor of urine KIM-1. Individually, age, sex, blood pressure, BCS, SDMA, SCr, phosphorus, TT4 and mid-sagittal kidney length were not significant predictors of urine KIM-1. In a multivariate model, if combined with USG, SDMA concentration was predictive (P = 0.030) of urine KIM-1.

Urine concentration was significantly correlated with urine KIM-1, which will be an important consideration when interpreting findings in cats with potential kidney injury.

Incidence of acute kidney injury (AKI) remained relatively stable over the last decade and the adjusted risks for it and mortality are similar across different continents and regions. Also, the mortality of septic-AKI can reach 70% in critically-ill patients. These sole facts can give rise to a question: is there something we do not understand yet? Currently, there are no specific therapies for septic AKI and the treatment aims only to maintain the mean arterial pressure over 65mmHg by ensuring a good fluid resuscitation and by using vasopressors, along with antibiotics. On the other hand, there is an increased concern about the different hemodynamic changes in septic AKI versus other forms and the link between the gut microbiome and the severity of septic AKI. Fortunately, progress has been made in the form of administration of pre- and probiotics, short chain fatty acids (SCFA), especially acetate, and also broad-spectrum antibiotics or selective decontaminants of the digestive tract in a successful attempt to modulate the microbial flora and to decrease both the severity of AKI and mortality. In conclusion, septic-AKI is a severe form of kidney injury, with particular hemodynamic changes and with a strong link between the kidney and the gut microbiome. By modulating the immune response we could not only treat but also prevent severe forms. The most difficult part is to categorize patients and to better understand the key mechanisms of inflammation and cellular adaptation to the injury, as these mechanisms can serve in the future as target therapies.

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9on-off). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9on-on Cadherin6pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.

Acute kidney injury (AKI) is a condition characterized by a rapid decline in kidney function within a span of 48 hours. It is influenced by various factors including inflammation, oxidative stress, excessive calcium levels within cells, activation of the renin-angiotensin system, and dysfunction in microcirculation. Ischemia-reperfusion injury (IRI) is recognized as a major cause of AKI; however, the precise mechanisms behind this process are not yet fully understood and effective treatments are still needed. To enhance the accuracy of diagnosing AKI during its early stages, the utilization of innovative markers is crucial. Numerous studies suggest that certain noncoding RNAs (ncRNAs), such as long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), play a central role in regulating gene expression and protein synthesis. These ncRNAs are closely associated with the development and recovery of AKI and have been detected in both kidney tissue and bodily fluids. Furthermore, specific ncRNAs may serve as diagnostic markers and potential targets for therapeutic interventions in AKI. This review aims to summarize the functional roles and changes observed in noncoding RNAs during ischemic AKI, as well as explore their therapeutic potential.

The prevalence of chronic kidney disease (CKD) is highly increasing. Renal fibrosis is a common pathological feature in various CKD. Previous studies showed tubular cell senescence is highly involved in the pathogenesis of renal fibrosis. However, the inducers of tubular senescence and the underlying mechanisms have not been fully investigated. C-X-C motif chemokine receptor 4 (CXCR4), a G-protein-coupled seven-span transmembrane receptor, increases renal fibrosis and plays an important role in tubular cell injury. Whereas, whether CXCR4 could induce tubular cell senescence and the detailed mechanisms have not studied yet. In this study, we adopted adriamycin nephropathy and 5/6 nephrectomy models, and cultured tubular cell line. Overexpression or knockdown of CXCR4 was obtained by injection of related plasmids. We identified CXCR4 increased in injury tubular cells. CXCR4 was expressed predominantly in renal tubular epithelial cells and co-localized with adipose differentiation-related protein (ADRP) as well as the senescence-related protein P16INK4A . Furthermore, we found overexpression of CXCR4 greatly induced the activation of β-catenin, while knockdown of CXCR4 inhibited it. We also found that CXCR4 inhibited fatty acid oxidation and triggered lipid deposition in tubular cells. To inhibit β-catenin by ICG-001, an inhibitor of β-catenin, could significantly block CXCR4-suppressed fatty acid oxidation. Taken together, our results indicate that CXCR4 is a key mediator in tubular cell senescence and renal fibrosis. CXCR4 promotes tubular cell senescence and renal fibrosis by inducing β-catenin and inhibiting fatty acid metabolism. Our findings provide a new theory for tubular cell injury in renal fibrosis.

The pathogenesis of Diabetic kidney disease(DKD) involves pathological changes in both tubulo-interstitium and the glomerulus. Surprisingly, tubulo-interstitial fibrosis (TIF), does not develop significantly until the late stage of DKD. Here, it is demonstrated that PR domain-containing 16 (PRDM16) is a key to the low level of TIF in DKD. In the experiments, PRDM16 is upregulated in high glucose-treated renal tubular cells, DKD mouse kidneys, and renal biopsy of human DKD patients via activation of NF-κB signal pathway. High glucose-induced expression of fibrotic proteins in renal tubular cells is suppressed by PRDM16. Mechanistically, PRDM16 bound to the promotor region of Transient receptor potential ankyrin 1 (TRPA1) to transactivate its expression and then suppressed MAPK (P38, ERK1/2) activation and downstream expression of TGF-β1. Knockout of PRDM16 from kidney proximal tubules in mice blocked TRPA1 expression and enhanced MAPK activation, TGF-β1 production, TIF development, and DKD progression, whereas knock-in of PRDM16 has opposite effects. In addition, overexpression of PRDM16 or its induction by formononetin ameliorated renal dysfunction and fibrosis in db/db diabetic mice. Finally, the above finding are detected in renal biopsies of DKD patients. Together, these results unveil PRDM16/TRPA1 as the mechanism responsible for the low level of TIF in the early stage of DKD by suppressing and TGF-β1 expression.

Acute kidney injury (AKI) is a common clinical condition with various causes and is associated with increased mortality. Despite advances in supportive care, AKI increases not only the risk of premature death compared with the general population but also the risk of developing chronic kidney disease and progressing towards kidney failure. Currently, no specific therapy exists for preventing or treating AKI other than mitigating further injury and supportive care. To address this unmet need, novel therapeutic interventions targeting the underlying pathophysiology must be developed. New and well-designed clinical trials with appropriate end points must be subsequently designed and implemented to test the efficacy of such new interventions. Herein, we discuss predictive and prognostic enrichment strategies for patient selection, as well as primary and secondary end points that can be used in different clinical trial designs (specifically, prevention and treatment trials) to evaluate novel interventions and improve the outcomes of patients at a high risk of AKI or with established AKI.

Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and has a role in active solute transport, maintenance of electrochemical gradients, and regulation of fluid balance. Renal proximal tubular cells (PTCs) are the primary segment to reabsorb and secrete various solutes and take part in AKI initiation. Mitochondria, which are enriched in PTCs, are the main source of adenosine triphosphate (ATP) in cells as generated through oxidative phosphorylation. Mitochondrial dysfunction may result in reactive oxygen species (ROS) production, impaired biogenesis, oxidative stress multiplication, and ultimately leading to cell death. Even though mitochondrial damage and malfunction have been observed in both human kidney disease and animal models of AKI and CKD, the mechanism of mitochondrial signaling in PTC for AKI-to-CKD transition remains unknown. We review the recent findings of the development of AKI-to-CKD transition with a focus on mitochondrial disorders in PTCs. We propose that mitochondrial signaling is a key mechanism of the progression of AKI to CKD and potential targeting for treatment.

This study investigated the effects of hot and cold temperature on the renal function of people with chronic diseases, such as diabetes, hypertension, and chronic kidney disease, using large-scale clinical data.

We used retrospective cohort data from the Clinical Data Warehouse of the Seoul St Mary's Hospital, which contains clinical, diagnostic, laboratory, and other information about all patients who have visited the hospital since 1997. We obtained climate data from the Automated Synoptic Observing System of the Korea Meteorological Administration. The heat index was used as a measuring tool to evaluate heat exposure by indexing the actual heat that individuals feel according to temperature and humidity. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. To investigate changes in renal function trends with heat index, this study used generalized additive mixed models.

Renal function decreased linearly with increasing heat index after approximately 25°C, which was considered the flexion point of temperature. A linear decrease in the eGFR was observed with the effects of 0 to 5 lag days. Although there was a correlation observed between the decrease in eGFR and temperatures below -10°C, the results did not indicate statistical significance.

The results of our study provide scientific evidence that high temperatures affect the renal function of people with chronic diseases. These results can help prevent heat-related morbidity by identifying those who are more likely to develop renal disease and experience worsening renal function.

This retrospective study investigated whether repetitive exposure to intravenous iodinated contrast media (ICM) affects long-term renal function in patients who undergo curative surgery for early gastric cancer (EGC) collected from the Korean Health Insurance and Review Assessment (HIRA) database. Patients diagnosed with gastric cancer between January 2010 and December 2013 underwent regular computed tomography (CT) scans to monitor for extragastric recurrence. Patients who already had chronic kidney disease (CKD) before cancer diagnosis or had undergone chemotherapy or repeated surgery were excluded. A nested case-control study design was chosen to analyze the effect of repetitive ICM exposure to long-term renal function by comparing patients who developed CKD 2 years after cancer diagnosis and patients who did not. Among 59,971 patients collected according to inclusion and exclusion criteria, 1021 were diagnosed with CKD 2 years after cancer diagnosis. Using 1:5 matching after adjusting for age, sex and date of cancer diagnosis, 5097 control patients were matched to 1021 CKD patients. Conditional logistic regression showed that the number of CTs taken using ICM slightly increased the odds of CKD (odds ratio, 1.080; 95% confidence interval (CI): 1.059, 1.100; P < 0.0001). Thus, the administration of ICM might contribute to chronic renal function impairment.

To evaluate the value of contrast volume/glomerular filtration ratio (Vc/eGFR ratio) and urine Neutrophil Gelatinase-Associated Lipocalin (uNGAL) in predicting the progression contract associated-acute kidney injury (CA-AKI) to chronic kidney disease (CKD) in planned percutaneous coronary intervention (PCI) patients.

We examined 387 adult patients who had undergone planned percutaneous coronary intervention (PCI). We determined acute kidney injury (AKI) and chronic kidney disease (CKD) using the criteria set by the Kidney Disease: Improving Global Outcomes (KDIGO). We calculated the estimated glomerular filtration rate (eGFR) using the CKD-EPI formula based on serum creatinine levels. To determine the Vc/eGFR ratio, we considered the contrast medium volume and eGFR for each patient. Additionally, we measured urine NGAL levels using the ELISA method.

The percentage of CA-AKI patients who developed CKD after planned PCI was 36.36%. Within the CA-AKI to CKD group, the Vc/eGFR ratio was 2.82, and uNGAL levels were significantly higher at 72.74 ng/mL compared to 1.93 ng/mL for Vc/eGFR ratio and 46.57 ng/mL for uNGAL in the recovery CA-AKI group. This difference was statistically significant (p<0.001). Diabetic mellitus, urine NGAL concentration, and Vc/eGFR ratio were found to be independent factors in the progression of CA-AKI to CKD. The Vc/eGFR ratio and uNGAL showed predictive capabilities for progressing CA-AKI to CKD with an AUC of 0.884 and 0.878, respectively. The sensitivity was 81.3% for both, while the specificity was 89.3% for Vc/eGFR ratio and 85.7% for uNGAL.

The Vc/eGFR ratio and uNGAL were good predictors for CA-AKI to CKD in planned PCI patients.

Recent advances in multiparametric magnetic resonance imaging (MRI) allow multiple quantitative measures to assess kidney morphology, tissue microstructure, oxygenation, kidney blood flow, and perfusion to be collected in a single scan session. Animal and clinical studies have investigated the relationship between the different MRI measures and biological processes, although their interpretation can be complex due to variations in study design and generally small participant numbers. However, emerging themes include the apparent diffusion coefficient derived from diffusion-weighted imaging, T1 and T2 mapping parameters, and cortical perfusion being consistently associated with kidney damage and predicting kidney function decline. Blood oxygen level-dependent (BOLD) MRI has shown inconsistent associations with kidney damage markers but has been predictive of kidney function decline in several studies. Therefore, multiparametric MRI of the kidneys has the potential to address the limitations of existing diagnostic methods to provide a noninvasive, noncontrast, and radiation-free method to assess whole kidney structure and function. Barriers to be overcome to facilitate widespread clinical application include improved understanding of biological factors that impact MRI measures, development of a larger evidence base for clinical utility, standardization of MRI protocols, automation of data analysis, determining optimal combination of MRI measures, and health economic evaluation.

Caloric restriction is an effective intervention to protract healthspan and lifespan in several animal models from yeast to primates, including humans. Caloric restriction has been found to induce cardiometabolic adaptations associated with improved health and to delay the onset and progression of kidney disease in different species, particularly in rodent models. In both aging and obesity, fibrosis is a hallmark of kidney disease, and epithelial-mesenchymal transition is a key process that leads to fibrosis and renal dysfunction during aging. In this study, we used an aged and obese rat model to evaluate the effect of long-term (6 months) caloric restriction (-40%) on renal damage both from a structural and functional point of view. Renal interstitial fibrosis was analyzed by histological techniques, whereas effects on mesenchymal (N-cadherin, Vimentin, Desmin and α-SMA), antioxidant (SOD1, SOD2, Catalase and GSTP1) inflammatory (YM1 and iNOS) markers and apoptotic/cell cycle (BAX, BCL2, pJNK, Caspase 3 and p27) pathways were investigated using Western blot analysis. Our results clearly showed that caloric restriction promotes cell cycle division and reduces apoptotic injury and fibrosis phenotype through inflammation attenuation and leukocyte infiltration. In conclusion, we highlight the beneficial effects of caloric restriction to preserve elderly kidney function.

Ferroptosis is a recently recognized form of regulated cell death, characterized by iron-dependent accumulation of lipid peroxidation. Ample evidence has depicted that ferroptosis plays an essential role in the cause or consequence of human diseases, including cancer, neurodegenerative disease and acute kidney injury. However, the exact role and underlying mechanism of ferroptosis in fibrotic kidney remain unknown. Acyl-CoA synthetase long-chain family member 4 (ACSL4) has been demonstrated as an essential component in ferroptosis execution by shaping lipid composition. In this study, we aim to discuss the potential role and underlying mechanism of ACSL4-mediated ferroptosis of tubular epithelial cells (TECs) during renal fibrosis. The unbiased gene expression studies showed that ACSL4 expression was tightly associated with decreased renal function and the progression of renal fibrosis. To explore the role of ACSL4 in fibrotic kidney, ACSL4 specific inhibitor rosiglitazone (ROSI) was used to disturb the high expression of ACSL4 in TECs induced by TGF-β, unilateral ureteral obstruction (UUO) and fatty acid (FA)-modeled mice in vivo, and ACSL4 siRNA was used to knockdown ACSL4 in TGF-β-induced HK2 cells in vitro. The results demonstrated that inhibition and knockdown of ACSL4 effectively attenuated the occurrence of ferroptosis in TECs and alleviated the interstitial fibrotic response. In addition, the expression of various profibrotic cytokines all decreased after ROSI-treated in vivo and in vitro. Further investigation showed that inhibition of ACSL4 obviously attenuates the progression of renal fibrosis by reducing the proferroptotic precursors arachidonic acid- and adrenic acid- containing phosphatidylethanolamine (AA-PE and AdA-PE). In conclusion, these results suggest ACSL4 is essential for tubular ferroptotic death during kidney fibrosis development and ACSL4 inhibition is a viable therapeutic approach to preventing fibrotic kidney diseases.

To identify optimized MRI markers for evaluating chronic kidney disease (CKD) and renal interstitial fibrosis (IF).

This prospective study included 43 patients with CKD and 20 controls. The CKD group was divided into mild and moderate-to-severe subgroups based on pathological results. Scanned sequences included T1 mapping, R2* mapping, intravoxel incoherent motion imaging, and diffusion-weighted imaging. One-way analyses of variance were used to compare MRI parameters among groups. Correlations of MRI parameters with estimated glomerular filtration rate (eGFR) and renal IF were analyzed using age as covariates. The support vector machine (SVM) model was used to evaluate the diagnostic efficacy of multiparametric MRI.

Compared to control values, renal cortical apparent diffusion coefficient (cADC), medullary ADC (mADC), cortical pure diffusion coefficient (cDt), medullary Dt (mDt), cortical shifted apparent diffusion coefficient (csADC), and medullary sADC (msADC) values gradually decreased in the mild and moderate-to-severe groups, while cortical T1 (cT1) and medullary T1 (mT1) values gradually increased. Values of cADC, mADC, cDt, mDt, cT1, mT1, csADC, and msADC were significantly associated with eGFR and IF (p < 0.001). The SVM model indicated that multiparametric MRI combining cT1 and csADC can distinguish patients with CKD from controls with high accuracy (0.84), sensitivity (0.70), and specificity (0.92) (AUC: 0.96). Multiparametric MRI combining cT1 and cADC exhibited high accuracy (0.91), sensitivity (0.95), and specificity (0.81) for evaluating IF severity (AUC: 0.96).

Multiparametric MRI combining T1 mapping and diffusion imaging may be of clinical utility in non-invasive assessment of CKD and IF.

This study shows that multiparametric MRI combining T1 mapping and diffusion imaging may be clinically useful in the non-invasive assessment of chronic kidney disease (CKD) and interstitial fibrosis; this could provide information for risk stratification, diagnosis, treatment, and prognosis.

• Optimized MRI markers for evaluating chronic kidney disease and renal interstitial fibrosis were investigated. • Renal cortex/medullary T1 values increased as interstitial fibrosis increased; cortical shifted apparent diffusion coefficient (csADC) correlated significantly with eGFR and interstitial fibrosis. • Support vector machine (SVM) combining cortical T1 (cT1) and csADC/cADC effectively identifies chronic kidney disease and accurately predicts renal interstitial fibrosis.

To evaluate follow-up care of critically ill patients with acute kidney injury (AKI).

Retrospective cohort study.

Patients admitted to the intensive care unit (ICU) with AKI in Alberta, Canada from 2005 to 2018, who survived to discharge without kidney replacement therapy or estimated glomerular filtration rate <15 mL/min/1.73 m2.

AKI (defined as ≥50% or ≥0.3 mg/dL serum creatinine increase).

The primary outcome was the cumulative incidence of an outpatient serum creatinine and urine protein measurement at 3 months postdischarge. Secondary outcomes included an outpatient serum creatinine or urine protein measurement or a nephrologist visit at 3 months postdischarge.

Patients were followed from hospital discharge until the first of each outcome of interest, death, emigration from the province, kidney replacement therapy (maintenance dialysis or kidney transplantation), or end of study period (March 2019). We used non-parametric methods (Aalen-Johansen) to estimate the cumulative incidence functions of outcomes accounting for competing events (death and kidney replacement therapy).

There were 29,732 critically ill adult patients with AKI. The median age was 68 years (IQR, 57-77), 39% were female, and the median baseline estimated glomerular filtration rate was 72 mL/min/1.73 m2 (IQR, 53-90). The cumulative incidence of having an outpatient creatinine and urine protein measurement at 3 months postdischarge was 25% (95% CI, 25-26). At 3 months postdischarge, 64% (95% CI, 64-65) had an outpatient creatinine measurement, 28% (95% CI, 27-28) had a urine protein measurement, and 5% (95% CI, 4-5) had a nephrologist visit.

We lacked granular data, such as urine output.

Many critically ill patients with AKI do not receive the recommended follow-up care. Our findings highlight a gap in the transition of care for survivors of critical illness and AKI.

Kidney disease is a growing public health problem worldwide, including both acute and chronic forms. Existing therapies for kidney disease target various pathogenic mechanisms; however, these therapies only slow down the progression of the disease rather than offering a cure. One of the potential and emerging approaches for the treatment of kidney disease is mesenchymal stromal/stem cell (MSC) therapy, shown to have beneficial effects in preclinical studies. In addition, extracellular vesicles (EVs) released by MSCs became a potent cell-free therapy option in various preclinical models of kidney disease due to their regenerative, anti-inflammatory, and immunomodulatory properties. However, there are scarce clinical data available regarding the use of MSC-EVs in kidney pathologies. This review article provides an outline of the renoprotective effects of MSC-EVs in different preclinical models of kidney disease. It offers a comprehensive analysis of possible mechanisms of action of MSC-EVs with an emphasis on kidney disease. Finally, on the journey toward the implementation of MSC-EVs into clinical practice, we highlight the need to establish standardized methods for the characterization of an EV-based product and investigate the adequate dosing, safety, and efficacy of MSC-EVs application, as well as the development of suitable potency assays.

The incidence of acute kidney injury following cardiac surgery (CSA-AKI) is up to 30%, and the risk of chronic kidney disease (CKD) has been found to be higher in these patients compared to the AKI-free population. The aim of our study was to assess the risk of major adverse kidney events (MAKE) [25% or greater decline in estimated glomerular filtration rate (eGFR), new hemodialysis, and death] after cardiac surgery in a Spanish cohort and to evaluate the utility of the score developed by Legouis D et al. (CSA-CKD score) in predicting the occurrence of MAKE.

This was a single-center retrospective study of patients who required cardiac surgery with cardiopulmonary bypass (CPB) during 2015, with a 1-year follow-up after the intervention. The inclusion criteria were patients over 18 years old who had undergone cardiac surgery [i.e., valve substitution (VS), coronary artery bypass graft (CABG), or a combination of both procedures].

The number of patients with CKD (eGFR < 60 mL/min) increased from 74 (18.3%) to 97 (24%) within 1 year after surgery. The median eGFR declined from 85 to 82 mL/min in the non-CSA-AKI patient group and from 73 to 65 mL/min in those with CSA-AKI (p = 0.024). Fifty-eight patients (1.4%) presented with MAKE at the 1-year follow-up. Multivariate logistic regression analysis showed that the only variable associated with MAKE was CSA-AKI [odds ratio (OR) 2.386 (1.31-4.35), p = 0.004]. The median CSA-CKD score was higher in the MAKE cohort [3 (2-4) vs. 2 (1-3), p < 0.001], but discrimination was poor, with a receiver operating characteristic curve (AUC) value of 0.682 (0.611-0.754).

Any-stage CSA-AKI is associated with a risk of MAKE after 1 year. Further research into new measures that identify at-risk patients is needed so that appropriate patient follow-up can be carried out.

The incidence of ureter obstruction is increasing and patients recovering from this kidney injury often progress to chronic kidney injury. There is evidence that a long-term consequence of recovery from ureter obstruction is an increased risk for salt-sensitive hypertension. A reversal unilateral ureteral obstruction (RUUO) model was used to study long-term kidney injury and salt-sensitive hypertension. In this model, we removed the ureteral obstruction at day 10 in mice. Mice were divided into four groups: (1) normal salt diet, (2) high salt diet, (3) RUUO normal salt diet, and (4) RUUO high salt diet. At day 10, the mice were fed a normal or high salt diet for 4 weeks. Blood pressure was measured, and urine and kidney tissue collected. There was a progressive increase in blood pressure in the RUUO high salt diet group. RUUO high salt group had decreased sodium excretion and glomerular injury. Renal epithelial cell injury was evident in RUUO normal and high salt mice as assessed by neutrophil gelatinase-associated lipocalin (NGAL). Kidney inflammation in the RUUO high salt group involved an increase in F4/80 positive macrophages; however, CD3+ positive T cells were not changed. Importantly, RUUO normal and high salt mice had decreased vascular density. RUUO was also associated with renal fibrosis that was further elevated in RUUO mice fed a high salt diet. Overall, these findings demonstrate long-term renal tubular injury, inflammation, decreased vascular density, and renal fibrosis following reversal of unilateral ureter obstruction that could contribute to impaired sodium excretion and salt-sensitive hypertension.

Ischemia/reperfusion injury (IRI) is a common cause of kidney damage, characterized by oxidative stress and inflammation. In this study, we investigated the potential protective effects of IAXO-102, a chemical compound, on experimentally induced IRI in male rats. The bilateral renal IRI model was used, with 24 adult male rats randomly divided into four groups (N=6): sham group (laparotomy without IRI induction), control group (laparotomy plus bilateral IRI for 30 minutes followed by 2 hours of reperfusion), vehicle group (same as control but pre-injected with the vehicle), and treatment group (similar to control but pre-injected with IAXO-102). We measured several biomarkers involved in IRI pathophysiology using enzyme-linked immunosorbent assay (ELISA), including High mobility group box1 (HMGB1), nuclear factor kappa b-p65 (NF-κB p65), interleukin beta-1 (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), 8-isoprostane, Bcl-2 associated X protein (BAX), heat shock protein 27 (HSP27), and Bcl-2. Statistical analysis was performed using one-way ANOVA and Tukey post hoc tests. Our results showed that IAXO-102 significantly improved kidney function, reduced histological alterations, and decreased the inflammatory response (IL-1, IL-6, and TNF) caused by IRI. IAXO-102 also decreased apoptosis by reducing pro-apoptotic Bax and increasing anti-apoptotic Bcl-2 without impacting HSP27. In conclusion, our findings suggest that IAXO-102 had a significant protective effect against IRI damage in the kidneys.

To date, imaging-guided multimodality therapy is important to improve the accuracy of the diagnosis of renal fibrosis, and nanoplatforms for imaging-guided multimodality diagnosis are gaining more and more attention. There are many limitations and deficiencies in clinical use for early-stage diagnosis of renal fibrosis, and multimodal imaging can contribute more thoroughly and provide in-detail information for effective clinical diagnosis. Melanin is an endogenous biomaterial, and we developed an ultrasmall particle size melanin nanoprobe (MNP-PEG-Mn) based on photoacoustic (PA) and magnetic resonance (MR) dual-modal imaging. MNP-PEG-Mn nanoprobe, with the average diameter about 2.7 nm, can be passively targeted for accumulation in the kidney, and it has excellent free radical scavenging and antioxidant abilities without further exacerbating renal fibrosis. Using the normal group signal as a control, the dual-modal imaging results showed that the MR imaging (MAI) and PA imaging (PAI) signals reached the strongest at 6 h when MNP-PEG-Mn entered the 7 day renal fibrosis group via the left vein of the tail end of the mice; however, the strength of the dual-modal imaging signal and the gradient of signal change were significantly weaker in the 28 day renal fibrosis group than in the 7 day renal fibrosis group and normal group. The phenomenon preliminarily indicates that as a PAI/MRI dual-modality contrast medium candidate, MNP-PEG-Mn has outstanding ability in clinical application potential.

Podocytes are exquisitely fashioned kidney cells that serve an essential role in the process of blood filtration. Congenital malformation or damage to podocytes has dire consequences and initiates a cascade of pathological changes leading to renal disease states known as podocytopathies. In addition, animal models have been integral to discovering the molecular pathways that direct the development of podocytes. In this review, we explore how researchers have used the zebrafish to illuminate new insights about the processes of podocyte ontogeny, model podocytopathies, and create opportunities to discover future therapies.