Eunjung Cho

Renoprotective effect of paricalcitol via a modulation of the TLR4-NF-κB pathway in ischemia/reperfusion-induced acute kidney injury.

BACKGROUND The pathophysiology of ischemic acute kidney injury (AKI) is thought to include a complex interplay between vascular endothelial cell dysfunction, inflammation, and tubular cell damage. Several lines of evidence suggest a potential anti-inflammatory effect of vitamin D in various kidney injury models. In this study, we investigated the effect of paricalcitol, a synthetic vitamin D analog, on renal inflammation in a mouse model of ischemia/reperfusion (I/R) induced acute kidney injury (AKI). METHODS Paricalcitol was administered via intraperitoneal (IP) injection at 24h before ischemia, and then I/R was performed through bilateral clamping of the renal pedicles. Twenty-four hours after I/R, mice were sacrificed for the evaluation of injury and inflammation. Additionally, an in vitro experiment using HK-2 cells was also performed to examine the direct effect of paricalcitol on tubular cells. RESULTS Pre-treatment with paricalcitol attenuated functional deterioration and histological damage in I/R induced AKI, and significantly decreased tissue neutrophil and macrophage infiltration and the levels of chemokines, the pro-inflammatory cytokine interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). It also decreased IR-induced upregulation of Toll-like receptor 4 (TLR4), and nuclear translocation of p65 subunit of NF-κB. Results from the in vitro study showed pre-treatment with paricalcitol suppressed the TNF-α-induced depletion of cytosolic IκB in HK-2 cells. CONCLUSION These results demonstrate that pre-treatment with paricalcitol has a renoprotective effect in ischemic AKI, possibly by suppressing TLR4-NF-κB mediated inflammation.

Role of inflammation in the pathogenesis of cardiorenal syndrome in a rat myocardial infarction model

BACKGROUND Cardiorenal syndrome is now frequently recognized, and the combined dysfunction of heart and kidney increases morbidity and mortality. This study aimed to investigate possible mechanisms that underlie renal damage following heart dysfunction using a rat myocardial infarction model, focusing on the inflammatory pathway. METHODS Rats were randomized into four groups: normal, volume depletion, sham operation and myocardial infarction (MI). MI was induced by the ligation of the left coronary artery and a volume depletion model was produced by low-salt diet and furosemide injection. Biochemical, histological and flow cytometric analyses were performed at 3 days and 4 and 8 weeks after MI. RESULTS On Day 3 following MI, the development of subclinical acute kidney injury was identified through significantly increased serum and urine neutrophil gelatinase-associated lipocalin level. We detected the increase of activated monocytes (CC chemokine receptor 2(+) ED-1(+)) in peripheral blood, along with the infiltration of ED-1(+) macrophages and the increment of nuclear p65 in the kidney of MI rats, suggesting the contribution of nuclear factor-kappa B-mediated inflammation in the development of Type 1 cardiorenal syndrome (CRS). The inflammatory cytokines, interleukin-6 and tumour necrosis factor-α (TNF-α) mRNA expression, as well as microvascular endothelial permeability and tubular cell apoptosis, significantly increased in the kidneys of MI rats. At 4 and 8 weeks after MI, tubular cell apoptosis, ED-1(+) macrophage infiltration and interstitial fibrosis increased in MI rats, and these chronic changes were significantly mitigated by systemic monocyte/macrophage depletion using liposome clodronate. CONCLUSION This study identifies the possible important role of inflammatory response as a mediator of heart-kidney crosstalk in CRS.

Glucocorticoids attenuate septic acute kidney injury.

BACKGROUND The incidence and mortality of septic acute kidney injury (AKI) remains high, whereas our understanding of pathogenesis for septic AKI is still limited. Glucocorticoids (GCs) have been clinically recommended for treatment of septic shock and also have showed favorable effect on septic AKI in several animal experiments. The aim of this study is to investigate the pathophysiology of septic AKI and the effect of GCs on septic AKI. METHODS We induced septic AKI using cecal ligation and puncture (CLP) model in 8-10 wk-old male C57BL/6 mice. Saline or dexamethasone (2.5 mg/kg) dissolved in saline was administered after surgery. Hemodynamic, biochemical and histological changes were examined in a time-course manner. RESULTS CLP resulted in hyperdynamic warm shock with multiple organ dysfunction including AKI. Despite renal dysfunction, light microscopy showed scanty acute tubular necrosis and inflammation. Instead, CLP induced significant increase in apoptosis of the kidney and spleen cells. In addition, septic kidneys showed mitochondrial injury and alterations in Bcl2 family proteins in the renal tubular cells. Dexamethasone treatment attenuated renal dysfunction, but it was not associated with improvement of hemodynamic parameters. Dexamethasone-induced organ protective effect was associated with reduced mitochondrial injury with preserved cytochrome c oxidase and suppression of proapoptotic proteins as well as reduced cytokine release. CONCLUSIONS Mitochondrial damage and subsequent apoptosis are thought to play important role in the development of septic AKI. GCs might be a useful therapeutic strategy for septic AKI by reducing mitochondrial damage and apoptosis.

The Role of Urinary Liver-Type Fatty Acid-Binding Protein in Critically Ill Patients

Although several urinary biomarkers have been validated as early diagnostic markers of acute kidney injury (AKI), their usefulness as outcome predictors is not well established. This study aimed to determine the diagnostic and prognostic abilities of urinary liver-type fatty acid-binding protein (L-FABP) in heterogeneous critically ill patients. We prospectively collected data on patients admitted to medical and surgical intensive care units (ICUs) from July 2010 to June 2011. Urine neutrophil gelatinase-associated lipocalin (NGAL) and L-FABP at the time of ICU admission were quantitated. Of the 145 patients, 54 (37.2%) had AKI defined by the Acute Kidney Injury Network (AKIN) criteria. AKI patients showed significantly higher level of urinary NGAL and L-FABP and also higher mortality than non-AKI patients. The diagnostic performances, assessed by the area under the ROC curve, were 0.773 for NGAL and 0.780 for L-FABP, demonstrating their usefulness in diagnosing AKI. In multivariate Cox analysis, urinary L-FABP was an independent predictor for 90-day mortality. Urinary L-FABP seems to be promising both for the diagnosis of AKI and for the prediction of prognosis in heterogeneous ICU patients. It needs to be further validated for clinical utility.

Urine Neutrophil Gelatinase-Associated Lipocalin Predicts Graft Outcome up to 1 Year After Kidney Transplantation

BACKGROUND Several recent reports demonstrated the usefulness of new biomarkers in early prediction of delayed graft function (DGF) and graft recovery after kidney transplantation (KT). It is unknown, however, whether these biomarkers would predict long-term graft outcome. In this study, we examined whether the biomarkers including neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP) can predict 1-year graft outcome as well as short-term graft function especially in patients with early graft function (EGF). METHODS This was a single-center, prospective observational study. Urine samples at 0 hours and 2 and 6 days were obtained and the level of NGAL and L-FABP were measured. RESULTS Of the 69 KT recipients enrolled, seven developed DGF, and the remaining 62 patients were finally enrolled as EGF recipients. EGF recipients were additionally divided into immediate graft function (IGF, n = 48) and slow graft function (SGF, n = 14) groups. Urinary NGAL (u-NGAL) level on day 2, but not L-FABP nor serum creatinine, was significantly higher in SGF compared to IGF group. Higher day 2 u-NGAL level was associated with more frequent development of SGF and, in addition, with significantly lower 1-year estimated glomerular filtration rate (eGFR). In multivariate logistic regression analysis, day 2 u-NGAL was a significant, independent factor for predicting poor long-term graft function (1-year eGFR < 60 mL/min/1.73 m(2)). CONCLUSIONS This study demonstrates the possibility that u-NGAL might be useful in predicting adverse 1-year outcome as well as short-term graft function even in EGF patients.

Soluble CD25 is increased in patients with sepsis‐induced acute kidney injury

Sepsis has been shown to induce the expansion of CD4+CD25+ regulatory T cells (Tregs), and this paradoxical immune suppression has been suggested to be closely associated with the development of sepsis‐induced organ dysfunction. In the present study, we aimed to investigate the possible link between immune suppression and the development of septic acute kidney injury (AKI).

Advanced chronic kidney disease: a strong risk factor for Clostridium difficile infection

Background/Aims: It has been suggested that chronic kidney disease (CKD) is a risk factor for Clostridium difficile infection (CDI) and is associated with increased mortality among patients infected with C. difficile. However, recent studies of the clinical impact of CKD on CDI in Asians are still insufficient. We sought to determine the relationship between CKD and CDI in a Korean population. Methods: This was a single-center, retrospective case-control study. In total, 171 patients with CDI were included as cases and 342 age- and gender-matched patients without CDI were used as controls. We compared the prevalence of CKD in the study sample and identified independent risk factors that could predict the development or prognosis of CDI. Results: Independent risk factors for CDI included stage IV to V CKD not requiring dialysis (odds ratio [OR], 2.90) and end-stage renal disease requiring dialysis (OR, 3.34). Patients with more advanced CKD (estimated glomerular filtration rate < 30) and CDI showed higher in-hospital mortality and poorer responses to the initial metronidazole therapy. Conclusions: More advanced CKD is an independent risk factor for CDI and is associated with higher in-hospital mortality and poor treatment responses in CDI patients. Thus, in CKD patients, careful attention should be paid to the occurrence of CDI and its management to improve the outcome of CDI.

Hemophagocytic Syndrome in a Patient with Acute Tubulointerstitial Nephritis Secondary to Hepatitis A Virus Infection

Hepatitis A virus (HAV) infection is generally a self-limited disease, but the infection in adults can be serious, to be often complicated by acute kidney injury (AKI) and rarely by virus-associated hemophagocytic syndrome (VAHS). Our patient, a 48-yr-old man, was diagnosed with HAV infection complicated by dialysis-dependent AKI. His kidney biopsy showed acute tubulointerstitial nephritis with massive infiltration of activated macrophages and T cells, and he progressively demonstrated features of VAHS. With hemodialysis and steroid treatment, he was successfully recovered.

Postoperative Hemolytic Uremic Syndrome with Renal Cortical Necrosis Following Laparoscopic Hemicolectomy

Non-Shiga-like toxin-producing Escherichia coli (STEC) or atypical hemolytic uremic syndrome (aHUS) is observed in 5–10% of all hemolytic uremic syndrome (HUS) cases, and usually develops secondary to infections, malignancies, drugs, transplantation, pregnancy, and autoimmune disease. However, there has been no report on adult onset HUS initiated by surgical procedures except transplantation. We report a 66-year-old woman who incurred renal impairment on the first day after laparoscopic hemicolectomy. Hemolytic anemia, thrombocytopenia, absence of Shiga toxin associated disease, normal ADAMTS13 activity, and low serum C3 (not C4) were consistent with a diagnosis of aHUS. We performed plasma exchange with fresh frozen plasma. Nevertheless, deteriorated renal function was not recovered after the treatment. Although it is an uncommon postoperative complication, aHUS needs to be considered as a possible cause of acute kidney injury combined with thrombocytopenia and anemia after surgical procedures, considering its different treatment modality and poor outcomes.

Proinflammatory CD14(+)CD16(+) monocytes are associated with vascular stiffness in predialysis patients with chronic kidney disease.

Background Chronic inflammation is frequently noted in patients with chronic kidney disease (CKD) and contributes to the development and progression of cardiovascular diseases. Monocytes are heterogeneous populations of cells, and they can be divided into subtypes with different phenotypes and functions based on CD14 and CD16 positivity. This study examined whether the proinflammatory CD14+CD16+ monocyte subset expands in predialysis CKD patients, and also whether the expansion of these cells is closely associated with systemic inflammation and cardiovascular risk factors. Methods The percentages of proinflammatory CD14+CD16+ monocytes were analyzed in 111 predialysis CKD patients using a flow cytometer, and they were compared with brachial–ankle pulse wave velocity as well as the cytokine plasma levels and other clinical parameters. Results The proportion of CD14+CD16+ monocytes was significantly higher in patients with advanced stages of CKD than in patients with the early stages. Interleukin-6 levels were also high in patients with advanced stages of CKD. The expansion of CD14+CD16+ monocytes showed significant positive correlations with the high-sensitive C-reactive protein levels, and negative correlations with the levels of serum albumin, hemoglobin, and 25(OH)-vitamin D. In addition, the expansion of CD14+CD16+ monocytes was an independent factor correlated with brachial–ankle pulse wave velocity in diabetic CKD patients. Conclusion Expansion of the proinflammatory CD14+CD16+ monocyte subset partially accounts for chronic inflammation, malnutrition, and atherosclerosis in CKD.