The furosemide stress test and computational modeling identify renal damage sites associated with predisposition to acute kidney injury in rats

Casanova, Alfredo G.; Fuentes‐Calvo, Isabel; Hernández-Sánchez, María Teresa; Quintero, Miguel; Toral, Paula; Caballero, María Teresa Caballero; Martı́nez-Salgado, Carlos; Morales, Ana Isabel; Eleno, Nélida; López‐Hernández, Francisco J.

doi:10.1016/j.trsl.2020.11.011

Cited by 11 publications

(29 citation statements)

References 45 publications

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“…the tubular functional reserve). In agreement with this, as we showed previously, [21] the FST is a very sensitive but low-resolution tubule injury test. Accordingly, the FST is very useful for detecting subtle alterations, but additional biomarkers are needed to inform damage granularity.…”

Section: Discussionsupporting

confidence: 92%

“…no damage takes place) showed reduced furosemideinduced diuresis and K + excretion. [21] In the present study, we observed that, during two weeks after overt damage has occurred, the urine output and K + urinary excretion forced by furosemide are also signi cantly reduced, thus denoting that there are still alterations in tubular function that mostly affect its response capacity (i.e. the tubular functional reserve).…”

Section: Discussionsupporting

confidence: 46%

“…Alterations in the furosemide stress test parallel post-AKI predisposition to AKI For its sensitivity to detect minimal and subclinical tubular alterations, [21] we applied the FST on AKI rats during the AKI episode and after pCr normalisation. Figure 6 shows that a profoundly reduced response to the FST (decreased urine output and urinary K + excretion) is produced by cisplatin during AKI.…”

Section: Resultsmentioning

confidence: 99%

“…The furosemide stress test (FST) was used to evaluate tubular integrity, as previously described. [21] Brie y, a single dose of furosemide (20 mg/kg, i.p.) was administered to rats, and they were immediately allocated in metabolic cages to collect individual urine during the following hour.…”

Section: Renal Function Studiesmentioning

confidence: 99%

“…Rats with damaged tubuli show lower furosemide-induced urinary volume and K + excretion, compared to control rats. [21] Histological studies Paraformaldehyde-xed kidney samples were immersed in para n, cut into 5 μm-thick slices and stained with haematoxylin and eosin (HE) and with Periodic acid-Schiff (PAS). Whole-kidney images were obtained with photographs taken using the DotSlide virtual microscopy technique (Olympus BX51, Olympus Iberia, Barcelona, Spain).…”

Section: Renal Function Studiesmentioning

confidence: 99%

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WITHDRAWN: Subclinical Sequelae of acute Kidney Injury Predispose To Acute Kidney Injury In Rats: Diagnostic Biomarkers

Fuentes‐Calvo¹,

Cuesta²,

Sancho-Martínez³

et al. 2021

Preprint

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Background. Acute kidney injury (AKI) is a risk factor for new AKI episodes and progression to chronic kidney disease, cardiovascular events and death, as under certain circumstances renal repair is maladaptive leading to proinflammatory and profibrotic signals. The definition for AKI recovery is based on increases in plasma creatinine, but it only happens when 50-70 % of nephrons have been lost. There are no studies monitoring the real state of structural and functional recovery after an AKI episode. We analysed the functional and structural sequelae after an episode of AKI in rats, whether and for how long animals retain enhanced sensibility to AKI and whether such a condition may be detected by known biomarkers of subclinical renal damage.Methods. We performed a cisplatin (5mg/kg body weight)-induced AKI in rats and, after recovery, we studied the renal susceptibility to new AKI episodes after treatment with subtoxic doses of gentamicin (50 mg/kg).Results. One week after the recuperation of a cisplatin-induced AKI, the kidneys show histological alterations (cast formation, necrosis and tubular dilatation), and predisposition to new AKI episodes after subtoxic gentamicin treatment. Tubular function (urine output and urinary excretion of K+, assessed by the furosemide tubular function test) remains affected despite the recovery of renal filtration after the AKI episode. Several urinary biomarkers detect this subclinical damage: albumin, transferrin, insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2). The increased [TIMP-2]*[IGFBP7] urinary excretion predicts new AKI episodes before gentamicin subtoxic treatment.Conclusions. After a cisplatin-induced AKI, the kidneys are in functional risk for new AKI episodes, which can be prevented by monitoring IGFBP7 and TIMP-2 urinary excretion. Our findings require subsequent clinical validation to verify the potential of these biomarkers in predicting future episodes of kidney damage.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 46%

Section: Resultsmentioning

confidence: 99%

Section: Renal Function Studiesmentioning

confidence: 99%

Section: Renal Function Studiesmentioning

confidence: 99%

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WITHDRAWN: Subclinical Sequelae of acute Kidney Injury Predispose To Acute Kidney Injury In Rats: Diagnostic Biomarkers

Fuentes‐Calvo¹,

Cuesta²,

Sancho-Martínez³

et al. 2021

Preprint

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Urinary GM2AP coincides with renal cortical damage and grades cisplatin nephrotoxicity severity in rats

Blanco-Gozalo,

Quiros,

Vicente-Vicente

et al. 2024

Toxicology

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Biomarkers of persistent renal vulnerability after acute kidney injury recovery

Fuentes‐Calvo

Cuesta

Sancho-Martínez

et al. 2021

Sci Rep

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Acute kidney injury (AKI) is a risk factor for new AKI episodes, chronic kidney disease, cardiovascular events and death, as renal repair may be deficient and maladaptive, and activate proinflammatory and profibrotic signals. AKI and AKI recovery definitions are based on changes in plasma creatinine, a parameter mostly associated to glomerular filtration, but largely uncoupled from renal tissue damage. The evolution of structural and functional repair has been incompletely described. We thus aimed at identifying subclinical sequelae persisting after recovery from cisplatin-induced AKI in rats. Compared to controls, after plasma creatinine recovery, post-AKI kidneys showed histological alterations and attendant susceptibility to new AKI episodes. Tubular function (assessed by the furosemide stress test, FST) also remained affected. Lingering parenchymal and functional subclinical alterations were paralleled by tapering, but abnormally high levels of urinary albumin, transferrin, insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and, especially, the [TIMP-2]*[IGFBP7] product. As subclinical surrogates of incomplete renal recovery, the FST and the urinary [TIMP-2]*[IGFBP7] product provide two potential diagnostic tools to monitor the sequelae and kidney vulnerability after the apparent recovery from AKI.

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The furosemide stress test and computational modeling identify renal damage sites associated with predisposition to acute kidney injury in rats

Cited by 11 publications

References 45 publications

WITHDRAWN: Subclinical Sequelae of acute Kidney Injury Predispose To Acute Kidney Injury In Rats: Diagnostic Biomarkers

WITHDRAWN: Subclinical Sequelae of acute Kidney Injury Predispose To Acute Kidney Injury In Rats: Diagnostic Biomarkers

Urinary GM2AP coincides with renal cortical damage and grades cisplatin nephrotoxicity severity in rats

Biomarkers of persistent renal vulnerability after acute kidney injury recovery

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