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Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury.

ABSTRACT: Acute kidney injury (AKI) is an underestimated, yet important, risk factor for the development of chronic kidney disease (CKD). Persistence of inflammation after a renal ischemic injury has been observed, both in experimental models and patients, and is thought to be an important mechanisms underlying progression of acute-to-chronic renal injury. Temporary suppression of inflammation immediately after AKI might therefore be a good first-line therapeutic strategy towards a better long term outcome. Male C57Bl/6?J mice (Charles River, 10-12?weeks of age) underwent warm (36?°C body temperature) unilateral ischemia-reperfusion of the kidney for 21?min, after which treatment with intraperitoneal injection of the corticosteroid dexamethasone (10?mg/kg) was initiated for 3?weeks. Both at that time point and after an additional 3?week post-treatment follow up period, fibrosis was quantified by collagen I gene expression and immunostaining, as well as gene expression analysis of fibrosis-related genes Tgf?, Ccn2 (Ctgf), Pai-1 and Ccn3. Furthermore, inflammation was evaluated by Tnf? gene expression and protein expression of the F4/80 macrophage marker and the ?-SMA fibroblast marker. Lastly, renal histopathology was quantified by a morphometric analysis of the tubulointerstitial area. Treatment with dexamethasone attenuated development of fibrosis, as evidenced by reduced collagen I gene expression and immunostaining, in combination with reduced gene expression of the pro-fibrotic Ccn2 and increased expression of the anti-fibrotic Ccn3. The effects of dexamethasone on renal fibrosis persisted during the 3?week follow up period, as evidenced by stagnation of collagen I deposition in the ischemic kidney, in contrast to vehicle-treatment, where progression of fibrosis was observed. However, expression levels of the pro-fibrotic genes re-approached those of vehicle-treated injured kidneys suggesting that the effects of dexamethasone on fibrosis beyond the treatment period are temporary. A short term anti-inflammatory therapy with dexamethasone only transiently attenuates ischemia induced fibrosis. Prolonged or persistent anti-inflammatory treatment seems warranted to achieve long term benefit.

SUBMITTER: Moonen L

PROVIDER: S-EPMC6276259 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury.

Moonen Lies L Geryl Hilde H D'Haese Patrick C PC Vervaet Benjamin A BA

BMC nephrology 20181203 1

<h4>Background</h4>Acute kidney injury (AKI) is an underestimated, yet important, risk factor for the development of chronic kidney disease (CKD). Persistence of inflammation after a renal ischemic injury has been observed, both in experimental models and patients, and is thought to be an important mechanisms underlying progression of acute-to-chronic renal injury. Temporary suppression of inflammation immediately after AKI might therefore be a good first-line therapeutic strategy towards a bett ...[more]

PMID: 30509215

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Project description:ObjectivePrompt assessment of perioperative complications is critical for the comprehensive care of surgical patients. Acute kidney injury requiring dialysis (AKI-D) is associated with high mortality, yet little is known about how long-term outcomes of patients have evolved. The association of AKI-D with postsurgical outcomes has not been well studied.MethodsWe investigated patients from the National Health Insurance Research Database and validated by the multicenter Clinical Trial Consortium for Renal Diseases cohort. All patients with AKI-D 18 years or older undergoing four major surgeries (cardiothoracic, esophagus, intestine, and liver) were retrospectively investigated (N=106,573). Patient demographics, surgery type, comorbidities before admission, and postsurgical outcomes, including the in-hospital, 30-day, and long-term mortality together with dialysis dependence were collected.ResultsAKI-D is the top risk factor for 30-day and long-term mortality after major surgery. Of 1,664 individuals with AKI-D and 6,656 matched controls, AKI-D during the hospital stay was associated with in-hospital (adjusted hazard ratio [aHR]=3.04, 95% CI 2.79-3.31), 30-day (aHR=3.65, 95% CI 3.37-3.94), and long-term (aHR=3.22, 95% CI 3.01-3.44) mortality. Patients undergoing cardiothoracic surgery (CTS) showed less in-hospital (aHR=0.85, 95% CI 0.75-0.97), 30-day (aHR=0.79, 95% CI 0.70-0.89), and long-term (aHR=0.80, 95% CI 0.72-0.90) mortality compared with non-CTS patients with AKI-D. CTS patients had a high risk of 30-day dialysis dependence (subhazard ratio [sHR]=1.67, 95% CI 1.18-2.38), but the risk of long-term dialysis dependence was similar (sHR=1.38, 95% CI 0.96-2.00) after AKI-D by taking mortality as a competing risk. Non-CTS patients had more comorbidities of sepsis, azotemia, hypoalbuminemia, and metabolic acidosis compared with CTS patients.ConclusionAKI exhibits paramount effects on postsurgical outcomes that extend well beyond discharge from the hospital. The goal of the perioperative assessment should include the reassurance of enhancing renal function recovery among different surgeries, and optimized follow-up is warranted in attenuating the complications after postsurgical AKI has occurred.

Project description:BackgroundKidney involvement is common in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). It tends to be aggressive, and in some patients, the kidney involvement may reach the criteria of acute kidney injury (AKI). Here, we aim to describe the clinical characteristics of these patients and find risk factors for poor outcomes.MethodsPatients diagnosed with AAV in our hospital from February 2003 to February 2017 were included. Those who reached the KDIGO AKI criteria were reclassified according to the KDIGO AKI stage. The clinical features of these patients were analyzed. Also, according to the variation of serum creatinine 3 months after AKI episode, patients were further divided into two groups: patients whose serum creatinine (Scr) level at the third month decreased by 30% or more from the peak Scr level was classified into G1 and others were classified into G2. Long-term renal and survival outcomes of these patients were analyzed with a Cox model. The renal endpoint was reaching end-stage renal disease (ESRD), and the survival endpoint was death. Nomograms were built based on cox models.ResultsOf 141 AAV patients included, during the median follow-up period of 64.0 (IQR 34.8, 85.4) months, 36 (25.5%) patients reached renal endpoints, and 22 (15.6%) patients died. The median renal survival time was 35.9 (IQR 21.3, 72.6) months and the median survival time was 48.4 (IQR 26.8, 82.8) months. Multivariate analysis showed that poor recovery of Scr level at 90 days (P < 0.001, RR = 9.150, 95%CI 4.163-20.113), BVAS score (P = 0.014, RR = 1.110, 95% CI1.021-1.207), and AKI stage 3 (P = 0.012 RR = 3.116, 95%CI 1.278-7.598) were independent risk factors for renal endpoints; poor recovery of Scr level at 90 days (P = 0.010, RR = 3.264, 95%CI 1.326-8.035), BVAS score (P = 0.010, RR = 1.171, 95%CI 1.038-1.320) and age (P = 0.017, RR = 1.046, 95%CI 1.008-1.086) were independent risk factors for all-cause death. The c-index of nomograms is 0.830 for the renal outcome and 0.763 for the survival outcome.ConclusionKDIGO AKI stage 3 is the risk factor for ESRD in AAV patients with AKI. The BVAS score and level of kidney function recovery at 90 days are the independent risk factors for both ESRD and all-cause death and are of predictive value for the outcome.

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Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury.

Publications

Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury.

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