Abstract
BackgroundAcute 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.MethodsMale 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 Tgfβ, Ccn2 (Ctgf), Pai-1 and Ccn3. Furthermore, inflammation was evaluated by Tnfα gene expression and protein expression of the F4/80 macrophage marker and the α-SMA fibroblast marker. Lastly, renal histopathology was quantified by a morphometric analysis of the tubulointerstitial area.ResultsTreatment 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.ConclusionA 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.
Highlights
Acute kidney injury (AKI) is an underestimated, yet important, risk factor for the development of chronic kidney disease (CKD)
Progression from AKI to CKD in untreated and vehicletreated animals As depicted in Fig. 1, renal unilateral ischemia-reperfusion injury (UIRI) without contralateral nephrectomy induced a significant reduction of renal mass as compared to sham-operated animals (3.29 ± 0.29 mg/g vs. 6.04 ± 0.58 mg/g) (p < 0.05) 3 weeks after UIRI
The weights of the contralateral uninjured kidney increased after UIRI in untreated animals as compared to sham (7.21 ± 0.45 mg/g vs. 6.36 ± 0.73 mg/g) (p < 0.05), which is in accordance with the physiological fact that the contralateral kidney becomes hypertrophic to compensate for the loss of function of the ischemic kidney (Fig. 1)
Summary
Acute kidney injury (AKI) is an underestimated, yet important, risk factor for the development of chronic kidney disease (CKD) [1]. Long-term follow-up studies (4 months to 6 years) report that between 35 and 71% of patients surviving an episode of AKI had incomplete recovery of renal function as assessed by creatinine clearance or serum creatinine measurements [2]. These patients are more likely to progress to end-stage renal disease (ESRD) as compared to patients without a history of either AKI or CKD [1] and contribute to the growing population of CKD patients. We previously optimized a mouse model of AKI to CKD by unilateral ischemia-reperfusion (UIRI) without contralateral nephrectomy, with development of moderate renal fibrosis and significant long-term inflammation [6]
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