Hye Min Choi

Distinct pathophysiologic mechanisms of septic acute kidney injury: role of immune suppression and renal tubular cell apoptosis in murine model of septic acute kidney injury.

Objective:Sepsis is the most common cause of acute kidney injury in critically ill patients; however, the mechanisms leading to acute kidney injury in sepsis remain elusive. Although sepsis has been considered an excessive systemic inflammatory response, clinical trials that inhibit inflammation have been shown to have no effect. The purpose of this study was to examine the pathophysiology of septic acute kidney injury focusing on immune responses and renal tubular cell apoptosis by providing an on-site quantitative comparison between septic- and ischemia/reperfusion-induced acute kidney injury. Design:Twenty-four hours after cecal ligation and puncture or ischemia/reperfusion injury, biochemical, histologic, and cytokine changes were compared in C57BL/6 mice. Apoptosis was assessed, and the effect of caspase 3 inhibition on renal function was also examined. The percentage of regulatory T cells and the effect of depletion were determined and compared with ischemia/reperfusion-induced acute kidney injury. The effect of interleukin-10 blocking was also compared. Measurements and Main Results:Despite comparable renal dysfunction, acute tubular necrosis or inflammation was minimal in septic kidneys. However, tubular cell apoptosis was prominent, and caspase 3 activity was positively correlated with renal dysfunction. A decrease in apoptosis by caspase 3 inhibitor resulted in attenuation of renal dysfunction. In assessment of systemic immunity, septic acute kidney injury was associated with an increase in interleukin-10, and also showed massive immune cell apoptosis with increased regulatory T cells. In contrast to ischemia/reperfusion injury in which depletion of regulatory T cells aggravated renal injury, depletion of regulatory T cells before cecal ligation and puncture resulted in renoprotection. In addition, blocking interleukin-10 rescued septic mice from the development of acute kidney injury, whereas it had no effect in ischemia/reperfusion injury. Conclusions:Pathogenesis of septic acute kidney injury is thought to be different from that of ischemia/reperfusion-induced acute kidney injury. Our data showed a link between apoptosis, immune suppression, and the development of acute kidney injury during sepsis and suggest that strategies targeting apoptosis or enhancing immunity might be a potential therapeutic strategy for septic acute kidney injury.

The role of Tregs and CD11c+ macrophages/dendritic cells in ischemic preconditioning of the kidney

Dendritic cells have the potential to induce tolerance and here we attempted to identify their role in the tolerance seen in ischemic pre-conditioning. We induced bilateral renal ischemic preconditioning in mice and then challenged them with an ischemic insult 7 days later. Compared to sham-operated controls, preconditioned mice were found to have reduced injury with less inflammation, but had an increased number of regulatory T cells (Tregs) in their kidneys after the delayed insult. Splenocytes from these mice had more Tregs and mature CD11c(+) cells, but reduced proliferative and cytokine-secretory responses, suggesting a state of immunosuppression compared to control mice. Anti-CD25 depletion followed by adoptive transfer of Tregs partially mitigated and then restored the protective effect of preconditioning. Depletion of CD11c(+) cells with liposomes containing clodronate was associated with partial loss of preconditioning benefits. The increased numbers of Tregs or impaired immune response found in splenocytes from preconditioned mice were partially reversed in splenocytes from liposome clodronate-treated animals, suggesting that CD11c(+) cells contribute to immune cell-mediated ischemic preconditioning. Hence, our results show that ischemic preconditioning of the kidney provides a negative signal to the peripheral immune system, partially mediating the tissue-protective and anti-inflammatory effects of this maneuver.

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.

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.

Altered monocyte-derived dendritic cell function in patients on hemodialysis: a culprit for underlying impaired immune responses

BackgroundPatients with end-stage renal disease (ESRD) are known to have impaired immune function. Dendritic cells (DCs) are the major antigen-presenting cells that initiate primary immune responses, linking innate and adaptive immunity. Although suboptimal immune responses to vaccination, as frequently observed in ESRD patients, might suggest the presence of impaired DC function, the precise nature of altered DC function is not fully understood.MethodsIn the current study, we compared the maturation status, viability, and function of monocyte-derived DCs (moDCs) of patients on hemodialysis (HD) with healthy controls.ResultsSurface expression of major histocompatibility complex class II, CD83, and CD86, and chemokine receptor CCR7 in moDCs was not different between HD patients and healthy controls. No significant difference was detected in the viability of moDCs determined by expression of annexin V and propidium iodide between two groups. However, moDCs from HD patients produced significantly higher amounts of IL-6 when stimulated by cytokine cocktails compared to healthy controls. In addition, mature moDCs from HD patients showed significantly enhanced allogeneic T-cell proliferation compared to healthy controls.ConclusionsOur data demonstrate aberrant DC function in HD patients and suggest that this might contribute to impaired immune responses.

Microinflammation in Hemodialysis Patients Is Associated with Increased CD14+CD16+ Pro-Inflammatory Monocytes: Possible Modification by On-Line Hemodiafiltration

Background: An increased percentage of pro-inflammatory CD14+CD16+ monocytes might contribute to inflammation in hemodialysis (HD) patients. The purpose of the study was to evaluate the possible contribution of pro-inflammatory monocytes to inflammation in HD patients and also to evaluate the effect of on-line hemodiafiltration (HDF). Methods: Flow cytometric detection of monocytes in patients undergoing HD, on-line HDF and healthy controls as well as plasma cytokines and cytokine mRNA measurement were performed. Results: Percent pro-inflammatory monocytes, plasma cytokines and cytokine mRNA significantly increased in HD patients. Intracellular cytokine staining showed pro-inflammatory monocytes were the predominant source of tumor necrosis factor-α. Percent pro-inflammatory monocytes positively correlated with plasma inflammatory cytokines. Percent pro-inflammatory monocytes, plasma cytokines and cytokine mRNA significantly decreased in on-line HDF patients. Conclusion: Increased pro-inflammatory monocytes are likely to contribute to inflammation in HD patients, and beneficial effect of on-line HDF might be partially mediated by modulating the inflammatory response.

Urine Liver-Type Fatty Acid-Binding Protein Predicts Graft Outcome up to 2 Years After Kidney Transplantation

BACKGROUND Several new biomarkers for the detection of early tubular injury have been investigated in kidney transplant recipients. We recently identified day 2 urinary neutrophil gelatinase-associated lipocalin (NGAL) as a predictor of slow graft function and adverse 1-year outcome. In the present study, we further investigated the value of urinary NGAL and liver-type fatty acid binding protein (L-FABP) for predicting long-term graft outcomes up to 2 years. METHODS This study was a single-center, prospective observational study. Serial urinary NGAL and L-FABP levels at 0 hours, 2 days, and 6 days after kidney transplantation (KT) were measured, and the clinical data were assessed during the 2-year period after KT. RESULTS During the 2-year follow-up period, 13 (18.8%), 5 (7.2%), and 4 (5.8%) patients were diagnosed with acute T-cell-mediated rejection, acute antibody-mediated rejection (AMR) and chronic AMR, respectively. In addition, 10 patients (14.3%) developed calcineurin inhibitor toxicity and 6 (8.7%) developed BK viremia. The mean estimated glomerular filtration rates (eGFR) at 1 and 2 years after KT were 65.1 ± 19.1 and 58.5 ± 22.6 mL/min/1.73 m(2), respectively, When poor long-term graft function was defined as eGFR of less than 50 mL/min/1.73 m(2) at 2 years, elderly donors, acute rejection, and high 0-hour urinary L-FABP levels were significant risk factors. Furthermore, in rejection-free patients, L-FABP was strongly associated with poor long-term graft function (P = .006). Multivariate logistic regression analysis showed that high 0-hour L-FABP (P = .015) and acute rejection (P = .006) were independent factors predicting poor long-term graft function. Receiver operating characteristic analysis showed that the area under the curve for urinary L-FABP was 0.692 (P = .036). CONCLUSIONS Our results suggest that urinary L-FABP may be a useful predictor of adverse long-term outcomes in KT patients.

Etiology and outcomes of anuria in acute kidney injury: a single center study

Background It was previously known that anuric acute kidney injury (AKI) is uncommon and its occurrence suggests complete ureteral obstruction, shock, or a major vascular event. As the epidemiology of AKI has significantly changed over the past decade, it is possible that the incidence, etiology, or clinical characteristics of anuric AKI have also changed. Methods A prospective cohort study was conducted that included all patients undergoing renal replacement therapy (RRT) for AKI during a 2-year period in a tertiary hospital. Patients were classified as having anuric, oliguric, or nonoliguric AKI based on their volume of urine when RRT started using the modified Acute Kidney Injury Network criteria. Results Of the 203 patients included in the study, 21.2% met the criteria for anuric AKI. Septic and postoperative AKI were the main causes of anuric AKI, with 60.5% of incidences occurring in hospital. Anuric AKI was associated with a younger age, a lower prevalence of pre-morbid chronic kidney disease and diabetes, more frequent continuous RRT requirement, and multi-organ dysfunction. In addition, patients with anuric AKI had a higher rate of in-hospital mortality and long-term dependence on RRT than patients with nonanuric AKI. Conclusion Anuric AKI is common, with sepsis as the main etiological insult, and is associated with adverse outcomes among patients with AKI who require RRT.

High estimated glomerular filtration rate is associated with coronary artery calcification in middle-aged Korean men without chronic kidney disease

BACKGROUND High estimated glomerular filtration rate (eGFR) as well as low eGFR is associated with cardiovascular morbidity and mortality. Vascular calcification is a suggested link between low eGFR and worse cardiovascular outcome. However, the association between high eGFR and vascular calcification is not known. The aim of this study is to investigate the relationship between high eGFR and coronary artery calcification (CAC). METHODS This cross-sectional study analyzed middle-aged Korean men in whom coronary artery calcium scores (CACS) and eGFR were measured as part of a health examination program in Korea. Participants with underlying chronic kidney disease (CKD), cardiovascular disease (CVD) and cancer were excluded. CAC was defined as a CACS >100. RESULTS Among 6986 subjects [age 48.1 (46.5-50.5) years], 321 (4.6%) participants had CAC. The percentages of participants with CAC were 5.7, 3.8, 4.9 and 6.6 in groups with eGFR (mL/min/1.73 m(2)) of 60 ∼ 74, 75 ∼ 89, 90 ∼ 104 and 105 ∼ max, respectively. According to multivariate analysis, the odds ratio for CAC in the group with eGFR of 105 ∼ max compared with the group with eGFR of 75 ∼ 89 was 2.52 (1.67-3.79, P < 0.001) after adjustment for age, body mass index, diabetes, hypertension, systolic blood pressure, glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, hsCRP, calcium, phosphorus, current smoking, alcohol intake and vigorous exercise frequency. CONCLUSIONS High eGFR is associated with CAC in middle-aged Korean men without CKD. Further studies are needed to verify a causal relationship and clarify the role of high eGFR in the development of CVD.

Chronic kidney disease in neurogenic bladder

It was believed that neurogenic bladder (NB) might be a risk factor of chronic kidney disease (CKD). However, data are limited regarding the real incidence or risk of CKD in NB. In addition, serum creatinine (sCr), a classical marker of renal function, is not reliable in NB patients because they present muscle wasting due to disuse or denervation. The aim of the study was to estimate the prevalence of CKD in NB patients using serum Cystatin‐C. Secondly, we aimed to identify the risk factors for CKD development in NB.