Repeated Episodes of Ischemia/Reperfusion Induce Heme-Oxygenase-1 (HO-1) and Anti-Inflammatory Responses and Protects against Chronic Kidney Disease

Preconditioning episodes of ischemia/reperfusion (IR) induce protection against acute kidney injury (AKI), however their long-term effect still unknown. We evaluated AKI to chronic kidney disease (CKD) transition, after three-mild or three-severe episodes of IR. AKI was induced by single bilateral IR (1IR), or three episodes of IR separated by 10-day intervals (3IR) of mild (20 min) or severe (45 min) ischemia. Sham-operated rats served as controls. During 9-months, the 1IR group (20 or 45 min) developed CKD evidenced by progressive proteinuria and renal fibrosis. In contrast, the long-term adverse effects of AKI were markedly ameliorated in the 3IR group. The acute response in 3IR, contrasted with the 1IR group, that was characterized by an increment in heme oxygenase-1 (HO-1) and an anti-inflammatory response mediated by a NFkB-p65 phosphorylation and IL-6 decrease, together with an increase in TGF-β, and IL-10 expression, as well as in M2-macrophages. In addition, three episodes of IR downregulated endoplasmic reticulum (ER) stress markers expression, CHOP and BiP. Thus, repeated episodes of IR with 10-day intervals induced long-term renal protection accompanied with HO-1 overexpression and M2-macrophages increase

Effect of Fosfomycin on Cyclosporine Nephrotoxicity

Fosfomycin (Fos) has emerged as a potential treatment against multidrug-resistant organisms, however, there has been little work done on its influence on calcineurin inhibitor nephrotoxicity (CIN). This study was designed to evaluate the effect of Fos in combination with cyclosporine (CsA) on CIN. Two sets of experiments were undertaken. In the first, Wistar rats received different doses of Fos: 0, 62.5, 125, 250, and 500 mg/kg. In the second, rats were divided into four groups: control, CsA 15 mg/kg s.c., CsA + fosfomycin 62.5 mg/kg (CsA + LF), and CsA + Fos 500 mg/kg (CsA + HF). CsA was administrated daily for 14 days, whereas Fos administration started on the ninth day followed by two more doses, delivered 48 h apart. The administration of different Fos doses did not alter renal function. In contrast, CsA induced arteriolopathy, hypoperfusion, a reduction in the glomerular filtration rate, and downregulation of eNOS, angiotensinogen, and AT1R mRNA levels. Lower doses of Fos did not modify CIN. Instead, the CsA + HF group exhibited greater hypoperfusion, arteriolopathy, and oxidative stress, and increased mRNA levels of pro-inflammatory cytokines. This study shows that Fos administered by itself at different doses did not cause renal injury, but when it was given repeatedly at high dosages (500 mg/kg) in combination with CsA, it increased CIN through the promotion of greater oxidative stress and renal inflammation

SerpinA3K Deficiency Reduces Oxidative Stress in Acute Kidney Injury

We previously showed that SerpinA3K is present in urine from rats and humans with acute kidney injury (AKI) and chronic kidney disease (CKD). However, the specific role of SerpinA3K during renal pathophysiology is unknown. To begin to understand the role of SerpinA3K on AKI, SerpinA3K-deficient (KOSA3) mice were studied 24 h after inducing ischemia/reperfusion (I/R) and compared to wild type (WT) mice. Four groups were studied: WT+S, WT+IR, KOSA3+S, and KOSA3+IR. As expected, I/R increased serum creatinine and BUN, with a GFR reduction in both genotypes; however, renal dysfunction was ameliorated in the KOSA3+IR group. Interestingly, the increase in UH2O2 induced by I/R was not equally seen in the KOSA3+IR group, an effect that was associated with the preservation of antioxidant enzymes’ mRNA levels. Additionally, FOXO3 expression was initially greater in the KOSA3 than in the WT group. Moreover, the increase in BAX protein level and the decrease in Hif1a and Vegfa induced by I/R were not observed in the KOSA3+IR group, suggesting that these animals have better cellular responses to hypoxic injury. Our findings suggest that SerpinA3K is involved in the renal oxidant response, HIF1α/VEGF pathway, and cell apoptosis

Validation test for Hsp72 in a similar population in ICU.

<p>Use of cut-off value one day before AKI diagnosis (AKIN criteria). PPV = Positive Predictive Value. NPV = Negative Predictive Value.</p><p>Validation test for Hsp72 in a similar population in ICU.</p

Summary of baseline and clinical characteristics.

<p>Continuous values are represented as mean ± standard deviation; dichotomous values are <i>N</i> (%). AKI: Acute Kidney Injury. ICU: Intensive Care Unit. SLE: Systemic Lupus Erythematosus. APS: Antiphospholipid Syndrome.</p><p>Summary of baseline and clinical characteristics.</p

IL-18 in critically ill patients after ICU admission.

<p>A) Urinary IL-18 levels assessed by ELISA from AKI and no-AKI patients. Every point represents the biomarker value in each urine sample, and the lines depicted the mean and 95% confident interval. AVG = average of urinary IL-18 levels in no-AKI patients determinated at 1, 5, and 10 days after ICU admission. B) Specificity and sensitivity of IL-18 to detect AKI two days before the AKIN criteria, determined by ROC analysis. C) Specificity and sensitivity of IL-18 to detect AKI one day before the AKIN criteria, determined by ROC analysis.</p

Hsp72 in critically ill patients after their admission at ICU.

<p>A) Urinary Hsp72 levels assessed by ELISA from AKI and no-AKI patients. Every point represents the biomarker value in each urine sample, and the lines depicted the mean and 95% confident interval. AVG = average of urinary Hsp72 levels in no-AKI patients determinated at 1, 5, and 10 days after ICU admission. B) Specificity and sensitivity of Hsp72 to detect AKI two days before the AKIN criteria, determined by ROC analysis. C) Specificity and sensitivity of Hsp72 to detect AKI one day before the AKIN criteria, determined by ROC analysis.</p