The Impact of Preexisting Chronic Kidney Disease on the Severity and Recovery of Acute Kidney Injury

Lim, Sung Yoon; Ko, Yoon Sook; Lee, Hee Young; Yang, Ji Hyun; Kim, Myung Gyu; Jo, Sang Kyung; Cho, Won Yong

doi:10.1159/000487492

Cited by 6 publications

(8 citation statements)

References 24 publications

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“…This shows that even after the achievement of functional recovery, patients with persistently elevated urinary IGFBP7 are still at high risk of incident or progressive CKD. The observation that prolonged cell cycle arrest is associated with maladaptive repair and progressive fibrosis in animal models of AKI to CKD transition could also support our findings [16].…”

Section: Discussionsupporting

confidence: 86%

Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 as biomarkers of patients with established acute kidney injury

Cho

Lim

Yang

et al. 2020

Korean J Intern Med

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Background/Aims: Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been recently discovered and validated as sensitive biomarkers that can predict stage 2 or 3 acute kidney injury (AKI) development in high-risk patients. We aimed to assess whether these biomarkers could predict adverse outcomes and renal recovery in established AKI patients. Methods: This was a single-center study prospectively enrolling 124 patients diagnosed with AKI. TIMP-2, IGFBP7, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule 1 (KIM-1) levels were measured at the time of diagnosis and the predictive performance of short-term outcomes and renal recovery was assessed. Results: Patients were divided into 4 quartiles according to the initial urinary TIMP-2/IGFBP7 levels. Stage 3 AKI (odds ratio [OR], 17.86), classified by the Kidney Disease Improving Global Outcomes (KDIGO), as well as the third and fourth quartiles of TIMP-2/IGFBP7 (OR, 5.75 and 44.98, respectively), were found to be independent predictors of renal replacement therapy at the time of AKI diagnosis. In addition, KDIGO stage 3 AKI (OR, 2.468) or the third of fourth quartiles of urinary TIMP-2/IGFBP7 (OR, 1.896 and 3.622, respectively) were also found to be useful in predicting nonrecovery of renal function. In a separate analysis of patients with renal recovery at discharge, initial urinary TIMP-2/IGFBP7 or urinary IGFBP7 at discharge could also predict new-onset or progressive chronic kidney disease (CKD). Conclusions: In AKI patients, urine TIMP-2/IGFBP7 could serve as a biomarker for predicting adverse outcomes, renal recovery, or the development and progression of CKD.

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Section: Discussionsupporting

confidence: 86%

Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 as biomarkers of patients with established acute kidney injury

Cho

Lim

Yang

et al. 2020

Korean J Intern Med

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“…Lim et al . showed that IRI in a remnant kidney model increased G1 cell cycle arrest during the recovery phase and that treatment with a p53 inhibitor decreased the expression of G1 arrest markers, as well as fibrosis 28 . These results suggest that prolonged epithelial G1 cell cycle arrest might be partially responsible for impaired recovery from AKI superimposed on CKD.…”

Section: Discussionmentioning

confidence: 99%

Impact of aging on transition of acute kidney injury to chronic kidney disease

Kim

Yang

et al. 2019

Sci Rep

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Acute kidney injury (AKI) increases the risk of end stage renal disease among the elderly, but the precise underlying mechanism is unknown. We investigated the effects of aging on AKI-to-chronic kidney disease (CKD) transition, focusing on renal inflammation. Aged and young C57BL/6 mice were subjected to bilateral ischemia-reperfusion injury (IRI). Baseline proinflammatory cytokine levels of kidneys were elevated in aged mice. After IRI, aged mice also showed persistent M1 dominant inflammation, with increased proinflammatory cytokines during the recovery phase. Persistent M1 inflammation was associated with blunted activation of CSF-1/IRF4 signal for M1/M2 polarization, but in vitro macrophage polarization with cytokine stimulation was not different between young and aged mononuclear cells. The tubular expressions of cell cycle arrest markers increased in aged mice during recovery phase, and in vitro transwell experiments showed that mononuclear cells or M1 macrophages co-cultured with arrested proximal tubular cells at G1 phase significantly impaired M2 polarization, suggesting that prolonged G1 arrest might be involved in persistent M1 inflammation in aged mice. Finally, M1 dominant inflammation in aged mice resulted in fibrosis progression. Our data show that impaired M2 polarization partially driven by senescent tubule cells with cell-cycle arrest may lead to an accelerated progression to CKD in the elderly.

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“…Similarly, activation of prolonged cell-cycle arrest have also been reported in other experimental AKI models, but in this case, linked to fibrosis ( Yang et al, 2010 ). In IRI-AKI mice, treatment with a p53 inhibitor has demonstrated the importance of G1 cell-cycle arrest in the progression of fibrosis ( Lim et al, 2018 ). Another mechanism involved in senescence-mediated renal damage is related to the induction of SASP in injured tubular cells ( Acosta et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes

et al. 2021

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Acute kidney injury (AKI) is more frequent in elderly patients. Mechanisms contributing to AKI (tubular cell death, inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest) have been linked to cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular and pathological basis of the age-related increase in AKI incidence is not completely understood. To explore these mechanisms, experimental AKI was induced by folic acid (FA) administration in young (3-months-old) and old (1-year-old) mice, and kidneys were evaluated in the early phase of AKI, at 48 h. Tubular damage score, KIM-1 expression, the recruitment of infiltrating immune cells (mainly neutrophils and macrophages) and proinflammatory gene expression were higher in AKI kidneys of old than of young mice. Tubular cell death in FA-AKI involves several pathways, such as regulated necrosis and apoptosis. Ferroptosis and necroptosis cell-death pathways were upregulated in old AKI kidneys. In contrast, caspase-3 activation was only found in young but not in old mice. Moreover, the antiapoptotic factor BCL-xL was significantly overexpressed in old, injured kidneys, suggesting an age-related apoptosis suppression. AKI kidneys displayed evidence of cellular senescence, such as increased levels of cyclin dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA damage response marker γH2AX. Furthermore, p21cip1 mRNA expression and nuclear staining for p21cip1 and γH2AX were higher in old than in young FA-AKI mice, as well as the expression of senescence-associated secretory phenotype (SASP) components (Il-6, Tgfb1, Ctgf, and Serpine1). Interestingly, some infiltrating immune cells were p21 or γH2AX positive, suggesting that molecular senescence in the immune cells (“immunosenescence”) are involved in the increased severity of AKI in old mice. In contrast, expression of renal protective factors was dramatically downregulated in old AKI mice, including the antiaging factor Klotho and the mitochondrial biogenesis driver PGC-1α. In conclusion, aging resulted in more severe AKI after the exposure to toxic compounds. This increased toxicity may be related to magnification of proinflammatory-related pathways in older mice, including a switch to a proinflammatory cell death (necroptosis) instead of apoptosis, and overactivation of cellular senescence of resident renal cells and infiltrating inflammatory cells.

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The Impact of Preexisting Chronic Kidney Disease on the Severity and Recovery of Acute Kidney Injury

Cited by 6 publications

References 24 publications

Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 as biomarkers of patients with established acute kidney injury

Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 as biomarkers of patients with established acute kidney injury

Impact of aging on transition of acute kidney injury to chronic kidney disease

Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes

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