Urinary Cyclophilin A as Marker of Tubular Cell Death and Kidney Injury.

Ramio Cabello,Ana M Lopez-Diaz,Ana B Sanz,Ignacio Mahillo,Miguel Fontecha-Barriuso,Diego Martin-Sanchez,Carmen Gonzalez-Enguita,Alberto Ortiz,Maria D Sanchez-Niño,Susana Carrasco

doi:10.3390/biomedicines9020217

Ramio Cabello, Ana M Lopez-Diaz + Show 8 more

Open Access

https://doi.org/10.3390/biomedicines9020217

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Abstract

Background: Despite the term acute kidney injury (AKI), clinical biomarkers for AKI reflect function rather than injury and independent markers of injury are needed. Tubular cell death, including necroptotic cell death, is a key feature of AKI. Cyclophilin A (CypA) is an intracellular protein that has been reported to be released during necroptosis. We have now explored CypA as a potential marker for kidney injury in cultured tubular cells and in clinical settings of ischemia-reperfusion injury (IRI), characterized by limitations of current diagnostic criteria for AKI. Methods: CypA was analyzed in cultured human and murine proximal tubular epithelial cells exposed to chemical hypoxia, hypoxia/reoxygenation (H/R) or other cell death (apoptosis, necroptosis, ferroptosis) inducers. Urinary levels of CypA (uCypA) were analyzed in patients after nephron sparing surgery (NSS) in which the contralateral kidney is not disturbed and kidney grafts with initial function. Results: Intracellular CypA remained unchanged while supernatant CypA increased in parallel to cell death induction. uCypA levels were higher in NSS patients with renal artery clamping (that is, with NSS-IRI) than in no clamping (NSS-no IRI), and in kidney transplantation (KT) recipients (KT-IRI) even in the presence of preserved or improving kidney function, while this was not the case for urinary Neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, higher uCypA levels in NSS patients were associated with longer surgery duration and the incidence of AKI increased from 10% when using serum creatinine (sCr) or urinary output criteria to 36% when using high uCypA levels in NNS clamping patients. Conclusions: CypA is released by kidney tubular cells during different forms of cell death, and uCypA increased during IRI-induced clinical kidney injury independently from kidney function parameters. Thus, uCypA is a potential biomarker of kidney injury, which is independent from decreased kidney function.

Highlights

Acute kidney injury (AKI) is a multifactorial and multiphasic kidney disease characterized by a rapid decline in kidney function, resulting in the accumulation of metabolic waste and toxins [1]
Cyclophilin A (CypA) is released by kidney tubular cells exposed to diverse lethal stimuli inducing different forms of cell death, suggesting that it may clinically be useful in diverse conditions associated with acute kidney injury (AKI)
In this regard, increased Urinary levels of CypA (uCypA) levels were found in clinical situations of ischemiareperfusion injury (IRI)-induced kidney injury in which the functional impact of kidney injury could not be reliably assessed, and provided information different from urinary NGAL (uNGAL), uCypA appearing more sensitive to IRI (Figure 9)

Summary

Introduction

Acute kidney injury (AKI) is a multifactorial and multiphasic kidney disease characterized by a rapid decline in kidney function, resulting in the accumulation of metabolic waste and toxins [1]. Rather than “failure”, current diagnostic criteria for AKI rely on evidence of decreased kidney function and not on evidence of kidney injury [1]. Decreased urine output or increased serum creatinine (sCr) may be observed in functional situations in the absence of kidney injury. SCr may increase, due to functional reasons, in the absence of injury when drugs that decrease the tubular secretion of creatinine are prescribed or when nephroprotective drugs decrease hyperfiltration, without concomitant kidney injury. Despite the term acute kidney injury (AKI), clinical biomarkers for AKI reflect function rather than injury and independent markers of injury are needed. We have explored CypA as a potential marker for kidney injury in cultured tubular cells and in clinical settings of ischemiareperfusion injury (IRI), characterized by limitations of current diagnostic criteria for AKI. Urinary levels of CypA (uCypA) were analyzed in patients after nephron sparing surgery (NSS) in which the contralateral kidney is not disturbed and kidney grafts with initial function

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