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At least 19 recordsLinked to original sources
PubMed2006

Mechanistic biomarkers for cytotoxic acute kidney injury.

Acute kidney injury is a common condition and is associated with a high mortality rate. It has been recognised that routinely used measures of renal function, such as levels of blood urea nitrogen and serum creatinine, increase significantly only after substantial kidney injury occurs and then with a time delay. Insensitivity of such tests delays the diagnosis in humans, making it particularly challenging to administer putative therapeutic agents in a timely fashion. Furthermore, this insensitivity affects the evaluation of toxicity in preclinical studies by allowing drug candidates, which have low, but nevertheless important, nephrotoxic side effects in animals, to pass the preclinical safety criteria only to be found to be clinically nephrotoxic with great human costs. This review presents the current status of sensitive and specific biomarkers to detect preclinical and clinical renal injury and summarises the techniques used to quantitate these biomarkers in biological fluids.

Acute Kidney Injury↗
PubMed2007

Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury.

Acute kidney injury (AKI) is a major clinical problem in which a critical vascular, pathophysiological component is recognized. We demonstrated previously that mesenchymal stem cells (MSC), unlike fibroblasts, are significantly renoprotective after ischemia-reperfusion injury and concluded that this renoprotection is mediated primarily by paracrine mechanisms. In this study, we investigated whether MSC possess vasculoprotective activity that may contribute, at least in part, to an improved outcome after ischemia-reperfusion AKI. MSC-conditioned medium contains VEGF, HGF, and IGF-1 and augments aortic endothelial cell (EC) growth and survival, a response not observed with fibroblast-conditioned medium. MSC and EC share vasculotropic gene expression profiles, as both form capillary tubes in vitro on Matrigel alone or in cooperation without fusion. MSC undergo differentiation into an endothelial-like cell phenotype in culture and develop into vascular structures in vivo. Infused MSC were readily detected in the kidney early after reflow but were only rarely engrafted at 1 wk post-AKI. MSC attached in the renal microvascular circulation significantly decreased apoptosis of adjacent cells. Infusion of MSC immediately after reflow in severe ischemia-reperfusion AKI did not improve renal blood flow, renovascular resistance, or outer cortical blood flow. These data demonstrate that the unique vasculotropic, paracrine actions elicited by MSC play a significant renoprotective role after AKI, further demonstrating that cell therapy has promise as a novel intervention in AKI.

Acute Disease↗
PubMed2025

Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.

Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2-4. For decades, it has been known that female kidneys are less sensitive to AKI5,6. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment7,8. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP19,10, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.

Ferroptosis↗
PubMed2005

Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury.

Renal ischemia-reperfusion injury (IRI) is the leading cause of acute kidney injury [AKI; acute renal failure (ARF)] in native kidneys and delayed graft function in deceased donor kidney transplants. Serum creatinine rises late after renal IRI, which results in delayed diagnosis. There is an important need to identify novel biomarkers for early diagnosis and prognosis in renal IRI. Given the inflammatory pathophysiology of renal IRI, we used a protein array to measure 18 cytokines and chemokines in a mouse model of renal IRI at 3, 24, and 72 h postischemia. A rise in renal keratinocyte-derived chemokine (KC) was the earliest and most consistent compared with other molecules, with 3-h postischemia values being 9- and 13-fold greater than sham and normal animals, respectively. Histological changes were evident within 1 h of IRI but serum creatinine only increased 24 h after IRI. With the use of an ELISA, KC levels in serum and urine were highest 3 h postischemia, well before a significant rise in serum creatinine. The human analog of KC, Gro-alpha, was markedly elevated in urine from humans who received deceased donor kidney transplants that required dialysis, compared with deceased donor kidney recipients with good graft function and live donor recipients with minimal ischemia. Measurement of KC and its human analog, Gro-alpha, could serve as a useful new biomarker for ischemic ARF.

Acute Disease↗
PubMed2006

Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). The lack of early biomarkers for AKI has impaired our ability to intervene in a timely manner. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is recently demonstrated as an early biomarker of AKI after CPB, increasing 25-fold within 2 h and declining 6 h after surgery. In the present study, we tested whether interleukin-18 (IL-18) is a predictive biomarker for AKI in the same group of patients following CPB. Exclusion criteria included pre-existing renal insufficiency and nephrotoxin use. Serial urine samples were analyzed by enzyme-linked immunosorbent assay for IL-18 in 20 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 35 controls (age, race, and gender-matched patients who did not develop AKI after CPB). Using serum creatinine, AKI was detected only 48-72 h after CPB. In contrast, urine IL-18 increased at 4-6 h after CPB, peaked at over 25-fold at 12 h, and remained markedly elevated up to 48 h after CPB. The performance of IL-18 as demonstrated by area under the receiver operating characteristics curve for diagnosis of AKI at 4, 12, and 24 h after CPB was 61, 75, and 73% respectively. Also, on multivariate analysis, both IL-18 and NGAL were independently associated with number of days in AKI among cases. Our results indicate that IL-18 is an early, predictive biomarker of AKI after CPB, and that NGAL and IL-18 are increased in tandem after CPB. The combination of these two biomarkers may allow for the reliable early diagnosis and prognosis of AKI at all times after CPB, much before the rise in serum creatinine.

Acute Kidney Injury↗
PubMed2006

Renal parenchymal oxygenation and hypoxia adaptation in acute kidney injury.

The pathogenesis of acute kidney injury (AKI), formally termed acute tubular necrosis, is complex and, phenotypically, may range from functional dysregulation without overt morphological features to literal tubular destruction. Hypoxia results from imbalanced oxygen supply and consumption. Increasing evidence supports the view that regional renal hypoxia occurs in AKI irrespective of the underlying condition, even under circumstances basically believed to reflect 'direct' tubulotoxicity. However, at present, it is remains unclear whether hypoxia per se or, rather, re-oxygenation (possibly through reactive oxygen species) causes AKI. Data regarding renal hypoxia in the clinical situation of AKI are lacking and our current concepts regarding renal oxygenation during acute renal failure are presumptive and largely derived from experimental studies. There is robust experimental evidence that AKI is often associated with altered intrarenal microcirculation and oxygenation. Furthermore, renal parenchymal oxygen deprivation seems to participate in the pathogenesis of experimental AKI, induced by exogenous nephrotoxins (such as contrast media, non-steroidal anti-inflammatory drugs or amphotericin), sepsis, pigment and obstructive nephropathies. Sub-lethal cellular hypoxia engenders adaptational responses through hypoxia-inducible factors (HIF). Forthcoming technologies to modulate the HIF system form a novel potential therapeutic approach for AKI.

Adaptation, Physiological↗
PubMed2006

Extent of glomerular tubularization is an indicator of the severity of experimental acute kidney injury in mice.

BACKGROUND: Acute kidney injury (AKI) secondary to ischemia continues to be a major clinical problem due to its high morbidity and mortality, and limited treatment options. Animal models are critical to both the study of the pathophysiology of AKI and the development of new interventions. Although histological changes at the glomerulotubular junction have been described in AKI, we examined here whether the extent of glomerular tubularization correlates with the degree of renal insufficiency in this condition. METHODS: Groups of mice with ischemia/reperfusion AKI were utilized in which the severity of renal insufficiency was defined. The resulting level of glomerular tubularization was analyzed, and the involved cell type was identified by immunohistochemistry and electron microscopy. RESULTS: The extent of glomerular tubularization increased significantly with the degree of renal insufficiency. Low level glomerular tubularization was present in normal mouse kidneys, while it was more common and increasingly circumferential in mice with more severe loss of kidney function. The parietal monolayer of cuboidal cells in glomeruli was contiguous with proximal tubular cells, showing a well-developed luminal brush border and positive staining for proliferating cell nuclear antigen and Lotus tetragonolobus, a proximal tubular cell-specific lectin. CONCLUSION: Increased levels of glomerular tubularization represent a poorly understood response to ischemic AKI in mice. As such, this glomerular 'tubularization score' may be useful to complement standard injury scores in experimental and, if detected, in clinical AKI.

Acute Disease↗
PubMed2006

Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects.

Acute kidney injury (AKI) occurs in about half of patients in septic shock and the mortality of AKI with sepsis is extremely high. An effective therapeutic intervention is urgently required. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that also have pleiotropic actions. They have been reported to increase the survival of septic or infectious patients. But the effect of simvastatin, a widely used statin, on sepsis-induced AKI is unknown. The effects of simvastatin and tumor necrosis factor (TNF)-alpha neutralizing antibody were studied in a clinically relevant model of sepsis-induced AKI using cecal ligation and puncture (CLP) in elderly mice. Simvastatin significantly improved CLP-induced mortality and AKI. Simvastatin attenuated CLP-induced tubular damage and reversed CLP-induced reduction of intrarenal microvascular perfusion and renal tubular hypoxia at 24 h. Simvastatin also restored towards normal CLP-induced renal vascular protein leak and serum TNF-alpha. Neither delayed simvastatin therapy nor TNF-alpha neutralizing antibody improved CLP-induced AKI. Simvastatin improved sepsis-induced AKI by direct effects on the renal vasculature, reversal of tubular hypoxia, and had a systemic anti-inflammatory effect.

Acute Kidney Injury↗
PubMed2006

Survival by dialysis modality in critically ill patients with acute kidney injury.

Among critically ill patients, acute kidney injury (AKI) requiring dialysis is associated with mortality rates generally in excess of 50%. Continuous renal replacement therapies (CRRT) often are recommended and widely used, although data to support its superiority over intermittent hemodialysis (IHD) are lacking. Data from the Program to Improve Care in Acute Renal Disease (PICARD), a multicenter observational study of AKI, were analyzed. Among 398 patients who required dialysis, the risk for death within 60 d was examined by assigned initial dialysis modality (CRRT [n = 206] versus IHD [n = 192]) using standard Kaplan-Meier product limit estimates, proportional hazards ("Cox") regression methods, and a propensity score approach to account for selection effects. Crude survival rates were lower for patients who were treated with CRRT than IHD (survival at 30 d 45 versus 58%; P = 0.006). Adjusted for age, hepatic failure, sepsis, thrombocytopenia, blood urea nitrogen, and serum creatinine and stratified by site, the relative risk for death associated with CRRT was 1.82 (95% confidence interval 1.26 to 2.62). Further adjustment for the propensity score did not materially alter the association (relative risk 1.92; 95% confidence interval 1.28 to 2.89). Among critically ill patients with AKI, CRRT was associated with increased mortality. Although the results could reflect residual confounding by severity of illness, these data provide no evidence for a survival benefit afforded by CRRT. Larger, prospective, randomized clinical trials to compare CRRT and IHD in severe AKI are needed.

Acute Disease↗
PubMed2006

Effect of off-pump coronary artery bypass graft surgery on postoperative acute kidney injury and mortality.

OBJECTIVE: Risk of mortality after cardiac surgery is associated with severity of acute kidney injury. The aim of this study is to examine the effect of off-pump coronary artery bypass surgery on the risk of postoperative acute kidney injury and its association with mortality. DESIGN: Observational cohort study. SETTING: Tertiary care center. PATIENTS: Some 10,061 patients underwent coronary artery bypass surgery (1998-2002), of which 1,365 patients underwent off-pump surgery. INTERVENTIONS: Acute kidney injury was defined as either requirement of dialysis or >/=50% decline in postoperative glomerular filtration rate but not requiring dialysis. We compared on- and off-pump surgeries and used propensity score matching to examine the effect of off-pump surgery on acute kidney injury and mortality. MEASUREMENTS AND MAIN RESULTS: We found that 2.6% on-pump and 1.2% off-pump patients developed acute kidney injury requiring dialysis among the 2,370 matched subjects (relative risk, 2.06; 95% confidence interval [CI], 1.36-3.36); 5.0% of on-pump patients suffered a >/=50% decline in glomerular filtration rate compared with 2.5% in off-pump group (relative risk, 2.00; 95% CI, 1.48-2.82). The mortality rate in the matched cohort was 2.3% for on-pump group vs. 0.6% in off-pump group (relative risk, 3.88; 95% CI, 2.29-9.50). Among matched patients with acute kidney injury, the risk of mortality was 13.14 (95% CI, 8.43-30.50) in patients requiring dialysis and 9.33 (95% CI, 4.83-19.00) in those with >/=50% decline in glomerular filtration rate but not requiring dialysis. CONCLUSIONS: Off-pump surgery is associated with a lower risk of developing acute kidney injury (regardless of its definition). The risk of mortality is incremental with worsening degrees of acute kidney injury. Lower risk of acute kidney injury may be one of the factors that offer a survival advantage after off-pump surgery.

Acute Kidney Injury↗
PubMed2006

RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis.

INTRODUCTION: The lack of a standard definition for acute kidney injury has resulted in a large variation in the reported incidence and associated mortality. RIFLE, a newly developed international consensus classification for acute kidney injury, defines three grades of severity--risk (class R), injury (class I) and failure (class F)--but has not yet been evaluated in a clinical series. METHODS: We performed a retrospective cohort study, in seven intensive care units in a single tertiary care academic center, on 5,383 patients admitted during a one year period (1 July 2000-30 June 2001). RESULTS: Acute kidney injury occurred in 67% of intensive care unit admissions, with maximum RIFLE class R, class I and class F in 12%, 27% and 28%, respectively. Of the 1,510 patients (28%) that reached a level of risk, 840 (56%) progressed. Patients with maximum RIFLE class R, class I and class F had hospital mortality rates of 8.8%, 11.4% and 26.3%, respectively, compared with 5.5% for patients without acute kidney injury. Additionally, acute kidney injury (hazard ratio, 1.7; 95% confidence interval, 1.28-2.13; P < 0.001) and maximum RIFLE class I (hazard ratio, 1.4; 95% confidence interval, 1.02-1.88; P = 0.037) and class F (hazard ratio, 2.7; 95% confidence interval, 2.03-3.55; P < 0.001) were associated with hospital mortality after adjusting for multiple covariates. CONCLUSION: In this general intensive care unit population, acute kidney 'risk, injury, failure', as defined by the newly developed RIFLE classification, is associated with increased hospital mortality and resource use. Patients with RIFLE class R are indeed at high risk of progression to class I or class F. Patients with RIFLE class I or class F incur a significantly increased length of stay and an increased risk of inhospital mortality compared with those who do not progress past class R or those who never develop acute kidney injury, even after adjusting for baseline severity of illness, case mix, race, gender and age.

Acute Kidney Injury↗
PubMed2026

Diagnostic and prognostic value of fibroblast growth factor 23 in acute kidney injury: systematic review and meta-analysis.

Background: Acute kidney injury (AKI) is associated with high mortality and adverse outcomes. Fibroblast growth factor 23 (FGF23) has emerged as a potential biomarker for AKI; however, its diagnostic and prognostic utility remains inconsistent.Methods: We conducted a systematic review and meta-analysis of studies evaluating circulating intact FGF23 (iFGF23) or C-terminal FGF23 (cFGF23) (PROSPERO: CRD42022302659). PubMed, EMBASE, CNKI, and Wanfang databases were searched through June 9, 2026. QUADAS-2 was used for quality assessment. A random-effects bivariate model pooled sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (SROC AUC).Results: Twenty-three studies were included: 17 diagnostic, 6 prognostic (one addressing both). For AKI diagnosis, the pooled sensitivity was 0.79 (95% CI 0.73-0.86), specificity 0.82 (95% CI 0.75-0.89), PLR 4.40 (95% CI 2.59-6.21), NLR 0.25 (95% CI 0.16-0.34), DOR 17.49 (95% CI 8.67-35.16), and SROC AUC 0.87 (95% CI 0.81-0.92). Substantial heterogeneity was observed (I2 = 67%), with iFGF23 demonstrating higher accuracy than cFGF23 (AUC 0.91 vs 0.81). For AKI mortality, pooled sensitivity was 0.77 (95% CI 0.69-0.84), specificity 0.76 (95% CI 0.70-0.82), DOR 10.89 (95% CI 6.86-17.30), and SROC AUC 0.77 (95% CI 0.70-0.83). Significant heterogeneity was noted (I2 = 86.2% for sensitivity, 80.4% for specificity). No significant publication bias was detected.Conclusions: Circulating FGF23 exhibits moderate-to-high diagnostic and moderate prognostic performance in AKI, though interpretation is limited by substantial heterogeneity. It may serve as a complementary biomarker for risk stratification, pending further validation with standardized protocols.

Humans↗
PubMed2005

Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.

The marginal effects of acute kidney injury on in-hospital mortality, length of stay (LOS), and costs have not been well described. A consecutive sample of 19,982 adults who were admitted to an urban academic medical center, including 9210 who had two or more serum creatinine (SCr) determinations, was evaluated. The presence and degree of acute kidney injury were assessed using absolute and relative increases from baseline to peak SCr concentration during hospitalization. Large increases in SCr concentration were relatively rare (e.g., >or=2.0 mg/dl in 105 [1%] patients), whereas more modest increases in SCr were common (e.g., >or=0.5 mg/dl in 1237 [13%] patients). Modest changes in SCr were significantly associated with mortality, LOS, and costs, even after adjustment for age, gender, admission International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis, severity of illness (diagnosis-related group weight), and chronic kidney disease. For example, an increase in SCr >or=0.5 mg/dl was associated with a 6.5-fold (95% confidence interval 5.0 to 8.5) increase in the odds of death, a 3.5-d increase in LOS, and nearly 7500 dollars in excess hospital costs. Acute kidney injury is associated with significantly increased mortality, LOS, and costs across a broad spectrum of conditions. Moreover, outcomes are related directly to the severity of acute kidney injury, whether characterized by nominal or percentage changes in serum creatinine.

Acute Disease↗
PubMed2006

Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists.

Acute kidney injury (AKI) is associated with a high degree of morbidity and mortality and its incidence is increasing. These factors, together with a lack of successful clinical trials, necessitate a comprehensive evaluation of the pathogenesis of AKI and trial design. The progress that has been made in elucidating the pathogenesis of AKI has defined inflammation as an early event and therefore a potential target for therapeutic intervention. This Review summarizes recent advances in our understanding of the role of inflammation in AKI as well as our approach to limiting inflammation using compounds that stimulate adenosine 2A receptors (A(2A)Rs). A(2A)Rs are members of a family of guanine nucleotide-binding proteins that have become a focus of interest primarily because of their ability to broadly inactivate the inflammatory cascade. An A(2A) agonist-ATL146 ester (ATL146e)-is currently being tested in a phase III clinical trial as a pharmacological stress agent in cardiac perfusion imaging studies. This study, together with extensively published preclinical data, will facilitate testing of ATL146e in human trials of AKI.

Adenosine A2 Receptor Agonists↗
PubMed2006

Acute kidney injury in critical care: time for a paradigm shift?

PURPOSE OF REVIEW: Acute alterations in renal function are commonly encountered in various settings with varied clinical manifestations ranging from a minimal elevation in serum creatinine to anuric renal failure. Our knowledge of human acute kidney injury has been fairly stagnant, until recently largely limited by a lack of concerted efforts in the field. This review summarizes the recent advances and provides an overview of emerging trends in this field. RECENT FINDINGS: One of the limitations in our knowledge of human acute kidney injury has been the lack of a standardized definition and staging criteria for this disorder. New information on the epidemiology and outcomes of acute kidney injury has emerged providing an opportunity to reappraise our approach to this disease. Also, there has been new work on the relationship of alterations of renal function to short and long-term outcomes, particularly mortality. SUMMARY: To translate advances from basic research to clinical application a multidisciplinary approach is required. New research in the field of biomarkers combined with clinical markers will lead to therapies that can be introduced earlier in the course of the disease and, hopefully, lead to a decrease in mortality from this potentially reversible condition.

Acute Kidney Injury↗
PubMed2006

Acute kidney injury: epidemiology and diagnostic criteria.

PURPOSE OF REVIEW: To review recent advances in the definitions and diagnostic criteria for acute renal failure and acute kidney injury. To explore how these changes impact the epidemiology and clinical implications for patients in the intensive care unit. RECENT FINDINGS: Recently published consensus criteria for the definition of acute renal failure/acute kidney injury have led to significant changes in how we think about this disorder. Studies from around the world, both in and out of the intensive care unit, have shown a dramatic incidence of acute kidney injury and high associated mortality. This review considers these new findings and their historical context, and attempts to shed new light on this old problem. SUMMARY: Small changes in kidney function in hospitalized patients are important and impact on outcome. RIFLE criteria provide a uniform definition of acute kidney injury and are increasingly used in literature.

Acute Kidney Injury↗