Acute Kidney Injury in Older Adults

Anderson, Sharon; Eldadah, Basil A.; Halter, Jeffrey B.; Hazzard, William R.; Himmelfarb, Jonathan; Horne, Frances Mc Farland; Kimmel, Paul L.; Molitoris, Bruce A.; N, Murthy M A; O’Hare, Ann M.; Schmader, Kenneth E.; High, Kevin P.

doi:10.1681/asn.2010090934

Cited by 182 publications

(144 citation statements)

References 177 publications

(81 reference statements)

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“…Aging has been linked to increased susceptibility to renal fibrosis (35)(36)(37)(38). A multitude of studies have now clearly established that aging is not merely a phenotypic manifestation but consists of specific gene expression changes associated with cellular senescence (39)(40)(41)(42).…”

Section: Resultsmentioning

confidence: 99%

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Leung

Wilson

Voltzke

et al. 2017

Molecular and Cellular Biology

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Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.

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Section: Resultsmentioning

confidence: 99%

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Leung

Wilson

Voltzke

et al. 2017

Molecular and Cellular Biology

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“…26 Moreover, the expression of biomarkers such as HAVCR1 and IL18 in body fluids may also be a sign of systemic trauma. 10,[27][28][29] The fact that two AKI, biomarkers HAVCR1 (KIM1) or IL18 were not identified as IRRATs by our initial statistical filtering strategy (fold change and FDR) yet were nevertheless associated with AKI phenotype, when re-analyzed, illustrates a caveat about reaching negative conclusions in microarray data. Arbitrary selection criteria may miss important associations when many features are highly correlated, and a comprehensive examination of the phenotype associations of all transcripts should be included.…”

Section: Discussionmentioning

confidence: 98%

“…5 The picture is further complicated in aging kidneys. 9,10 This prospective study of kidney transplants with AKI was undertaken to define the transcripts induced by human AKI and their clinical correlations. We previously analyzed the correlates of estimated GFR (eGFR) in transplant biopsies, but those were mainly late biopsies with atrophy-fibrosis, not AKI.…”

mentioning

confidence: 99%

Molecular Phenotypes of Acute Kidney Injury in Kidney Transplants

Famulski

Freitas²,

Kreepala³

et al. 2012

Journal of the American Society of Nephrology

134

146

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Little is known regarding the molecular phenotype of kidneys with AKI because biopsies are performed infrequently. However, all kidney transplants experience acute injury, making early kidney transplants an excellent model of acute injury, provided the absence of rejection, because donor kidneys should not have CKD, post-transplant biopsies occur relatively frequently, and follow-up is excellent typically. Here, we used histopathology and microarrays to compare indication biopsies from 26 transplants with acute injury with 11 pristine protocol biopsies of stable transplants. Kidneys with acute injury showed increased expression of 394 transcripts associated with the repair response to injury, including many epithelium-like injury molecules tissue, remodeling molecules, and inflammation molecules. Many other genes also predicted the phenotype, including the acute injury biomarkers HAVCR1 and IL18. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score in kidneys with acute injury correlated with reduced graft function, future renal recovery, brain death, and need for dialysis, but not with future graft loss. In contrast, histologic features of acute tubular injury did not correlate with function or with the molecular changes. Thus, the transcripts associated with repair of injury suggest a massive coordinated response of the kidney parenchyma to acute injury, providing both an objective measure for assessing the severity of injury in kidney biopsies and validation for many biomarkers of AKI.

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“…For this reason, morbidity and mortality rates in patients who develop AKI have remained stable or improved only slightly over the past several decades, whereas the incidence of AKI has steadily increased. 5,6 Whereas most studies of AKI have focused on the initiation of injury and its associated risk-factors and outcomes, there are fewer studies that address the biology and clinical patterns of recovery. To identify factors that might promote the repair phase after kidney injury, we performed a proteomic analysis of mouse urine after ischemia/reperfusion (I/R) injury.…”

mentioning

confidence: 99%

Chitinase-Like Protein Brp-39/YKL-40 Modulates the Renal Response to Ischemic Injury and Predicts Delayed Allograft Function

Schmidt

Hall

Kale

et al. 2013

Journal of the American Society of Nephrology

104

100

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Kidney hypoperfusion during episodes of systemic hypotension or after surgical procurement for transplantation can lead to tubular cell death via necrosis and apoptosis, which trigger a series of responses that promote repair. The factors that contribute to the repair phase after kidney injury are not well understood. Using a urine proteomic screen in mice, we identified the macrophage-secreted chitinase-like protein Brp-39, the murine protein product of the chitinase 3-like 1 gene, as a critical component of this reparative response that serves to limit tubular cell apoptotic death via activation of Akt, improving animal survival after kidney ischemia/reperfusion. Examination of graded times of renal ischemia revealed a direct correlation between the degree of kidney injury and both Chi3l1/Brp-39 expression in the kidney and its levels in the urine. In samples collected from patients undergoing deceased-donor kidney transplantation, we found higher levels of the orthologous human protein, YKL-40, in urine and blood from allografts subjected to sufficient peri-transplant ischemia to cause delayed graft function than from allografts with slow or immediate graft function. Urinary levels of YKL-40 obtained within hours of transplant predicted the need for subsequent dialysis in these patients. In summary, these data suggest that Brp-39/YKL-40 is a sensor of the degree of injury, a critical mediator of the reparative response, and a possible biomarker to identify patients at greatest risk of sustained renal failure after transplantation.

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Acute Kidney Injury in Older Adults

Cited by 182 publications

References 177 publications

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Molecular Phenotypes of Acute Kidney Injury in Kidney Transplants

Chitinase-Like Protein Brp-39/YKL-40 Modulates the Renal Response to Ischemic Injury and Predicts Delayed Allograft Function

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