Angiopoietin-2 inhibition attenuates kidney fibrosis by hindering chemokine C-C motif ligand 2 expression and apoptosis of endothelial cells.

Plasma levels of angiopoietin-2 are increased in patients with chronic kidney disease (CKD). Moreover, mouse models of progressive kidney disease also demonstrate increased angiopoietin-2 in both plasmas and kidneys. The role of dysregulated angiopoietins in the progression of kidney disease has not been thoroughly investigated. Here, we found in a cohort of 319 patients with CKD that plasma angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratios were positively associated with the development of kidney failure. In mice with progressive kidney disease induced by either ureteral obstruction or ischemia-reperfusion injury, overexpression of human angiopoietin-1 in the kidney tubules not only reduced macrophage infiltration in the initial stage post-injury but also attenuated endothelial cell apoptosis, microvascular rarefaction, and fibrosis in the advanced disease stage. Notably, angiopoietin-1 attenuated chemokine C-C motif ligand 2 (CCL2) expression in the endothelial cells of the fibrosing kidneys, and these protective effects led to attenuation of functional impairment. Mechanistically, angiopoietin-1 reduced CCL2-activated macrophage migration and protected endothelial cells against cell apoptosis induced by angiopoietin-2 and Wnt ligands. Based on this, we applied L1-10, an angiopoietin-2 inhibitor, to the mouse models of progressive kidney disease and found inhibitory effects on macrophage infiltration, microvascular rarefaction, and fibrosis. Thus, we defined the detrimental impact of increased angiopoietin-2 on kidney survival of patients with CKD which appears highlighted by angiopoietin-2 induced endothelial CCL2-activated macrophage infiltration and endothelial cell apoptosis in their kidneys undergoing fibrosis.

Is the rating result reliable? A new approach to respond to a medical trainee's concerns about the reliability of Mini-CEX assessment.

PURPOSE: Whether the rating result of mini-clinical evaluation exercise (Mini-CEX) for rating clinical skills is reliable is of a medical trainee's great concerns. The objectives of this study were to analyze the test-retest reliability, interrater reliability and internal consistency reliability of Mini-CEX. METHODS: Three clinical scenarios, each played by a standardized patient and resident, were developed and videotaped. A group of assessors were recruited to rate the resident's clinical skills using Mini-CEX with a nine-point grading scale in each videotaped clinical scenario. Each assessor was required: (1) to watch the videotaped clinical scenarios a sequential order; (2) to rate each medical trainee's clinical skills in each clinical scenario for two rating sessions, and there must be a minimum three-week interval between the first and the second Mini-CEX rating session. RESULTS: A total of 38 assessors participated in this study. This study showed that: (1) an assessor carried out similar rating reuslts under the same clinical performance based on an acceptable test-retest reliability (Pearson's correlation coefficients = 0.24-0.76, P value=<0.01-0.14); (2) assessors gave similar rating results to a medical trainee's clinical performance based on a good interrater reliability (intra-class correlation coefficient = 0.57-0.83, P value=<0.01-0.03); and (3) the items reflected unidimensionally a construct-a medical trainee's clinical skills based on an excellent internal consistency reliability (Cronbach's alpha = 0.92-0.97). CONCLUSION: This study convincingly showed that Mini-CEX is a reliable assessment tool for rating clinical skills, and can be widely used to assess medical trainees' clinical skills.

Spectrum of cancer patients receiving renal biopsy.

BACKGROUND: The frontier of onco-nephrology, particularly renal complications of cancer and treatment, remains unexplored. We revisit the fundamental tool of diagnosing kidney disease, renal biopsy, in cancer patients with renal manifestation. METHODS: Patients who received renal biopsy from July 2015 to July 2019 were analyzed. Primary outcomes included end-stage renal disease (ESRD), mortality, and catastrophic outcome defined as either ESRD or mortality. A Cox proportional hazards model and Kaplan-Meier technique were used to assess the association with outcome measurements and survival analyses. Immunosuppression after renal biopsy and response to the treatment were evaluated. RESULTS: Among the 77 patients, the median age was 66 years (interquartile range [IQR] 59-73 years) and 46 (59.7%) were male. At the time of renal biopsy, 57 patients (74%) had various degrees of renal insufficiency. Tubulointerstitial damage score, quantified by renal pathology, were associated with higher hazards of ESRD (hazard ratio [HR], 1.77; 95% confidence interval [95% CI], 1.20 to 2.61; P = 0.004) and catastrophic outcome (HR, 1.30; 95% CI, 0.99 to 1.70; P = 0.058). The response rate to immunosuppression was lower in those diagnosed with tubulointerstitial nephritis (1 of 4 patients, 25%) than those with glomerulopathy (10 of 20 patients, 50%). CONCLUSION: Renal biopsy may improve diagnostic accuracy and assist in treatment guidance of cancer patients with renal manifestation. Renal biopsy should be encouraged with clinical indication. Collaboration between oncologists and nephrologists is of paramount importance to provide more comprehensive care for caner patients.

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis.

Prolyl hydroxylase domain enzyme (PHD) inhibitors are effective in the treatment of chronic kidney disease (CKD)-associated anemia by stabilizing hypoxia inducible factor (HIF), thereby increasing erythropoietin and consequently erythropoiesis. However, concern for CKD progression needs to be addressed in clinical trials. Although pre-clinical studies showed an anti-inflammatory effect in kidney disease models, the effect of PHD inhibitors on kidney fibrosis was inconsistent probably because the effects of HIF are cell type and context dependent. The major kidney erythropoietin-producing cells are pericytes that produce erythropoietin through HIF-2α-dependent gene transcription. The concern for the impact of HIF in pericytes on kidney fibrosis arises from the fact that pericytes are the major precursor cells of myofibroblasts in CKD. Since cells expressing Gli1 fulfill the morphologic and anatomic criteria for pericytes, we induced Gli1+ cell-specific HIF stabilization or knockout to study the impact of HIF in pericytes on kidney pathology of mice with or without fibrotic injury induced by unilateral ureteral obstruction. Compared with the littermate controls, mice with pericyte-specific HIF stabilization due to von Hippel-Lindau protein or PHD2 knockout showed increased serum erythropoietin and polycythemia rather than a discernible difference in kidney fibrosis. Compared with Gli1+ pericytes sorted from littermate controls, Gli1+ pericytes sorted from PHD2 knockout mice showed increased erythropoietin gene expression rather than discernible changes in Col1a1 or Acta2 expression. Furthermore, pericyte-specific knockout of HIF-1α or HIF-2α did not affect kidney fibrosis. Thus, our study supports the absence of negative effects of PHD inhibitors on kidney fibrosis of mice despite HIF stabilization in pericytes.

Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis.

Peritoneal fibrosis remains a problem in kidney failure patients treated with peritoneal dialysis. Severe peritoneal fibrosis with encapsulation or encapsulating peritoneal sclerosis is devastating and life-threatening. Although submesothelial fibroblasts as the major precursor of scar-producing myofibroblasts in animal models and M2 macrophage (Mϕ)-derived chemokines in peritoneal effluents of patients before diagnosis of encapsulating peritoneal sclerosis have been identified, attenuation of peritoneal fibrosis is an unmet medical need partly because the mechanism for cross talk between Mϕs and fibroblasts remains unclear. We use a sodium hypochlorite-induced mouse model akin to clinical encapsulated peritoneal sclerosis to study how the peritoneal Mϕs activate fibroblasts and fibrosis. Sodium hypochlorite induces the disappearance of CD11bhigh F4/80high resident Mϕs but accumulation of CD11bint F4/80int inflammatory Mϕs (InfMϕs) through recruiting blood monocytes and activating local cell proliferation. InfMϕs switch to express chemokine (C-C motif) ligand 17 (CCL17), CCL22, and arginase-1 from day 2 after hypochlorite injury. More than 75% of InfMϕs undergo genetic recombination by Csf1r-driven Cre recombinase, providing the possibility to reduce myofibroblasts and fibrosis by diphtheria toxin-induced Mϕ ablation from day 2 after injury. Furthermore, administration of antibody against CCL17 can reduce Mϕs, myofibroblasts, fibrosis, and improve peritoneal function after injury. Mechanistically, CCL17 stimulates migration and collagen production of submesothelial fibroblasts in culture. By breeding mice that are induced to express red fluorescent protein in Mϕs and green fluorescence protein (GFP) in Col1a1-expressing cells, we confirmed that Mϕs do not produce collagen in peritoneum before and after injury. However, small numbers of fibrocytes are found in fibrotic peritoneum of chimeric mice with bone marrow from Col1a1-GFP reporter mice, but they do not contribute to myofibroblasts. These data demonstrate that InfMϕs switch to pro-fibrotic phenotype and activate peritoneal fibroblasts through CCL17 after injury. CCL17 blockade in patients with peritoneal fibrosis may provide a novel therapy. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Renin-angiotensin-aldosterone system inhibition decreased contrast-associated acute kidney injury in chronic kidney disease patients.

BACKGROUND/PURPOSE: Chronic kidney disease (CKD) is a risk factor for contrast associated acute kidney injury (CA-AKI). The risk of renin-angiotensin-aldosterone system inhibitor (RASi) use in patients with CKD before the administration of contrast is not clear. METHODS: In this nested case-control study, 8668 patients received contrast computed tomography (CT) from 2013 to 2018 during index administration in a multicenter hospital cohort. The identification of AKI is based on the Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria within 48 h after contrast medium used. RESULTS: Finally, 986 patients (age, 63.36 ± 12.22; men, 72.92%) with CKD (estimated glomerular filtration rate (eGFR) = 35.0 ± 19.8 mL/min/1.73 m2) were eligible for analysis. After the index date, RASi users (n = 315) were less likely to develop CA-AKI (13.65% vs 30.4%, p < 0.001), and had a lower hospital mortality (8.25% vs 19.23%, p < 0.001) compared with non-users. The pre-contrast use of RASi decrease the risk of AKI (OR, 0.342, p < 0.001) and hospital mortality (OR, 0.602, p = 0.045). Even a few defined daily doses (DDDs) of RASi treatment, more than 0.02 prior to contrast CT could attenuate CA-AKI. The hospital mortality was higher in RASi non-users if their eGFR value was more than 17.9 mL/min/1.73 m2. CONCLUSION: RASi use in patients with CKD prior to contrast CT has the potential to mitigate the incidence of AKI and hospital mortality. Even a low dose of RASi will noticeably decrease the risk of AKI and will not increase the risk of hyperkalemia.

Angiopoietin-2 is associated with metabolic syndrome in chronic kidney disease.

BACKGROUNDS: Metabolic syndrome is a subclinical status in promoting atherosclerotic cardiovascular disease and type 2 diabetes mellitus. The significance of metabolic syndrome and pathophysiology in chronic kidney disease is not investigated. METHODS: We enrolled adult patients with CKD stages 3 to 5 from December 2006 to December 2007. Metabolic syndrome was defined by the US National Cholesterol Education Programme Adult Treatment Panel III guidelines. Plasma levels of angiogenic growth factors were measured. Univariate and multivariate logistic regression analyses were used. RESULTS: Total 451 patients were analyzed with median estimated glomerular filtration rate of 27.0 ml/min per 1.73m2 (interquartile range 14.3-41.3). Patients with metabolic syndrome were older (P = 0.002), had higher percentage using diuretics (P = 0.002) but lower percentage using pentoxifylline (P = 0.017). Patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein (P < 0.0001), uric acid (P = 0.009) and angiopoietin-2 (P = 0.001). Multivariate logistic regression analyses revealed significant association between plasma levels of angiopoietin-2 and metabolic syndrome (P = 0.042). CONCLUSION: The prevalence of metabolic syndrome in advanced CKD was higher than general population. CKD patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein, uric acid and angiopoietin-2. Plasma levels of angiopoietin-2 were significantly associated with metabolic syndrome in patients with CKD. Metabolic syndrome in CKD may be not only a prognostic factor but also an interventional target, possibly through ameliorating inflammation. Prospective and interventional studies are necessary to establish the pathophysiology.

Nephrologist Follow-Up Care of Patients With Acute Kidney Disease Improves Outcomes: Taiwan Experience.

OBJECTIVES: Acute kidney injury (AKI) and acute kidney disease (AKD) are a continuum on a disease spectrum and frequently progress to chronic kidney disease. Benefits of nephrologist subspecialty care during the AKD period after AKI are uncertain. METHODS: Patients with AKI requiring dialysis who subsequently became dialysis independent and survived for at least 90 days, defined as the AKD period, were identified from the Taiwanese population's health insurance database. Cox proportional hazard models using death as the competing risk before and after propensity-score matching were applied to evaluate various endpoints. RESULTS: Among a total of 20 260 patients with AKI requiring dialysis who became dialysis independent, only 7550 (37.3%) patients were followed up with by a nephrologist (F/Unephrol group) during the AKD period. During a mean 4.04 ± 3.56 years of follow-up, the patients in the F/Unephrol group were more often administered statin, antihypertensives, angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), diuretics, antiplatelet agents, and antidiabetic agents. The patients in the F/Unephrol group had a lower mortality rate (hazard ratio [HR] = 0.87, P < .001) and were less likely to have major adverse cardiovascular events (MACE) (subdistribution HR [sHR] = 0.85, P < .001), congestive heart failure (CHF) (sHR = 0.81, P < .001), and severe sepsis (sHR = 0.88, P = .008) according to the Cox proportional model after adjusting for mortality as a competing risk. During the AKD period, an increase in the frequency of nephrology visits was associated with improved outcomes. CONCLUSIONS: In this population-based cohort, even after weaning off acute dialysis, only a minority of patients visited a nephrologist during the AKD period. We showed that nephrology follow-up is associated with a decrease in MACE, CHF exacerbations, and sepsis, as well as lower mortality; thus it may improve outcomes in patients with AKD.

Immediate knowledge improvement and long-term teaching confidence after general medicine faculty training program.

BACKGROUND/PURPOSE: This study analyzed the effects of the General Medicine Faculty Training Program (GMFTP), which was implemented in 2009. The training program includes a 7-hour basic training (BT) to introduce ways of teaching and assessing the 6 core competencies identified by the Accreditation Council for Graduate Medical Education, and a 40-hour clinical training program. METHODS: Physicians from different hospitals attended the GMFTPs. Since 2010, we have been using quick tests to assess trainees' familiarity of core competencies. Knowledge improvement (KI) was defined as the difference between post-BT and pre-BT test scores. Since 2013, we have been annually mailing questionnaires to assess trainees' teaching confidence (TC) of core competencies. We analyzed the correlations between trainees' characteristics, KIs, and TCs. RESULTS: Between year 2009 and 2017, a total of 319 attending physicians (257 male, 62 female), with a mean age of 39.1 ± 6.2 years, completed the GMFTPs. Significant KI (32.6-55.4) was noted. There were no correlations between trainees' characteristics and KIs. The mean TCs for the 6 core competences were all above 4.0 (based on a 5-point Likert scale). TCs were positively correlated with age during GMFTP training, age when responding to the questionnaire, and duration between training and the last time responding to the questionnaire. TC showed no correlation with sex, hospitals, departments, or KI. CONCLUSION: Knowledge of teaching core competencies improved immediately after BT, but KIs did not correlate with TCs in long-term follow-up. After the training program, physicians' teaching confidence increased over time.

Heart rate variability as a predictor of rapid renal function deterioration in chronic kidney disease patients.

AIM: Autonomic dysfunction contributes to cardiovascular morbidity/mortality and can be evaluated with heart rate variability (HRV). This study is to evaluate the prognostic significance of HRV on renal function in non-dialysis chronic kidney disease (CKD) patients. METHODS: We enrolled 326 non-dialysis CKD patients in this prospective observational study. The median follow-up period was 2.02 years. Five-minutes of electrocardiography recordings obtained at enrolment were reprocessed to assess HRV. Five frequency-domain measures and one time-domain measures were obtained. Rapid CKD progression was defined as annual estimated glomerular filtration rate (eGFR) loss over 30% per year or eGFR decline rate over 3 mL/min per 1.73 m2 per year. The prevalence of abnormal HRV, associated factors of HRV and impact of HRV on the risk of CKD progression were analyzed. RESULTS: The abnormality of HRV increased along with the severity of CKD. In patients with stage 5 CKD, the proportion of abnormal ln(low frequency power) (LF), ln(high frequency power) (HF), lnLF/HF were 69.5, 52.8 and 50%, respectively. Associated factors of HRV included advanced CKD, diabetes mellitus, serum albumin, severe proteinuria, Beck Anxiety Inventory score, erythropoietin use, renin-angiotensin system inhibitors and heart failure. Multivariate logistic regression model analysis revealed lower lnLF/HF, hypertension and severe proteinuria were the risk factors of rapid CKD progression. CONCLUSION: The prevalence of autonomic dysfunction measured by HRV among each stage CKD patients is different. Most patients in advanced CKD stage have reduced values of HRV parameters. The estimation of lnLF/HF also provided prognostic information on CKD progression in addition to classical risk factors.

Physician workload associated with do-not-resuscitate decision-making in intensive care units: an observational study using Cox proportional hazards analysis.

BACKGROUND: Physicians play a substantial role in facilitating communication regarding life-supporting treatment decision-making including do-not-resuscitate (DNR) in the intensive care units (ICU). Physician-related factors including gender, personal preferences to life-supporting treatment, and specialty have been found to affect the timing and selection of life-supporting treatment decision-making. This study aimed to examine the influence of physician workload on signing a DNR order in the ICUs. METHODS: This is retrospective observational study. The medical records of patients, admitted to the surgical ICUs for the first time between June 1, 2011 and December 31, 2013, were reviewed. We used a multivariate Cox proportional hazards model to examine the influence of the physician's workload on his/her writing a DNR order by adjusting for multiple factors. We then used Kaplan-Meier survival curves with log-rank test to compare the time from ICU admission to DNR orders written for patients for two groups of physicians based on the average number of patients each physician cared for per day during data collection period. RESULTS: The hazard of writing a DNR order by the attending physicians who cared for more than one patient per day significantly decreased by 41% as compared to the hazard of writing a DNR order by those caring for fewer than one patient (hazard ratio = 0.59, 95% CI 0.39-0.89, P = .01). In addition, the factors associated with writing a DNR order as determined by the Cox model were non-operative, cardiac failure/insufficiency diagnosis (hazard ratio = 1.71, 95% CI 1.00-2.91, P = .05) and the Therapeutic Intervention Scoring System score (hazard ratio = 1.02, 95% CI 1.00-1.03, P = .03). Physicians who cared for more than one patient per day were less likely to write a DNR order for their patients than those who cared for in average fewer than one patient per day (log-rank chi-square = 5.72, P = .02). CONCLUSIONS: Our findings highlight the need to take multidisciplinary actions for physicians with heavy workloads. Changes in the work environmental factors along with stress management programs to improve physicians' psychological well-being as well as the quality.

Are physicians on the same page about do-not-resuscitate? To examine individual physicians' influence on do-not-resuscitate decision-making: a retrospective and observational study.

BACKGROUND: Individual physicians and physician-associated factors may influence patients'/surrogates' autonomous decision-making, thus influencing the practice of do-not-resuscitate (DNR) orders. The objective of this study was to examine the influence of individual attending physicians on signing a DNR order. METHODS: This study was conducted in closed model, surgical intensive care units in a university-affiliated teaching hospital located in Northern Taiwan. The medical records of patients, admitted to the surgical intensive care units for the first time between June 1, 2011 and December 31, 2013 were reviewed and data collected. We used Kaplan-Meier survival curves with log-rank test and multivariate Cox proportional hazards models to compare the time from surgical intensive care unit admission to do-not-resuscitate orders written for patients for each individual physician. The outcome variable was the time from surgical ICU admission to signing a DNR order. RESULTS: We found that each individual attending physician's likelihood of signing do-not-resuscitate orders for their patients was significantly different from each other. Some attending physicians were more likely to write do-not-resuscitate orders for their patients, and other attending physicians were less likely to do so. CONCLUSION: Our study reported that individual attending physicians had influence on patients'/surrogates' do-not-resuscitate decision-making. Future studies may be focused on examining the reasons associated with the difference of each individual physician in the likelihood of signing a do-not-resuscitate order.

To examine the associations between medical students' conceptions of learning, strategies to learning, and learning outcome in a medical humanities course.

BACKGROUND: By learning medical humanities, medical students are expected to shift from handling the diseases only to seeing a whole sick person. Therefore, understanding medical students' learning process and outcomes of medical humanities becomes an essential issue of medical education. Few studies have been conducted to explore factors surrounding medical students' learning process and outcomes of medical humanities. The objectives were: (1) to investigate the relationships between medical students' conceptions of learning and strategies to learning; and (2) to examine the relationships between students' strategies to learning and learning outcomes for medical humanities. METHODS: We used the modified Approaches to Learning Medicine (mALM) questionnaire and Conceptions of Learning Medicine (COLM) questionnaire to measure the medical students' strategies to learning and conceptions of learning respectively. The learning outcome of medical humanities was measured using students' weighted grade in a medical humanities course. The confirmatory factor analysis (CFA) was used to validate the COLM and mALM questionnaires, in which construct validity and reliability were assessed. Pearson's correlation was used to examine the relationships among the factors of COLM, mALM, and the weighted grade. Path analysis using structural equation modeling technique (SEM) was employed to estimate the structural relationships among the COLM, mALM, and the weighted grade. RESULTS: Two hundred and seventy-five first-year medical students consented to participate in this study. The participants adopting surface strategies to learning were more likely to have unsatisfactory learning outcome (ß = - 0.14, p = .04). The basic-level conception of "Preparing for Testing" was negatively (ß = - 0.19, p < .01) associated with deep strategies of learning, and positively (ß = 0.48, p < .01) associated with surface strategies of learning (ß = 0.50, p < .01). The basic-level conception of "Skills Acquisition" was positively associated with deep strategies of learning (ß = 0.23, p < .01). CONCLUSION: Medical educators should wisely employ teaching strategies to increase students' engagement with deep and self-directed learning strategies, and to avoid using surface learning strategies in the medical humanities course in order to achieve better learning outcomes.

Application of high-fidelity simulation in critical care residency training as an effective learning, assessment, and prediction tool for clinical performance.

BACKGROUND/PURPOSE: This study was conducted to assess: 1) the impact of the HFS curriculum on residents' knowledge and skills, and 2) the correlation between learning outcomes and the clinical performance. METHODS: An HFS-based curriculum was implemented for junior residents prior to their ICU rotations. Residents completed written tests before (pre-test) and after (post-test) the curriculum and were assessed on their performance during the simulation sessions. Clinical performance was evaluated using global rating for knowledge, clinical skills, and leadership and decision-making skills. RESULTS: Complete data on pre-, post-test, simulation performance assessment, and clinical performance evaluation were available for 69 residents. Residents scored higher on their written post-test (64.6) compared with the pre-test (57.0) (p < 0.01). The simulation performance of residents improved between their first (3.43) and second (3.60) sessions (p < 0.05). Post-test scores correlated poorly with simulation performance (r = 0.03-0.28). Multivariable linear regression analysis revealed that clinical performance correlated better and significantly with simulation performance than the post-test for knowledge and clinical skills. CONCLUSION: HFS is an effective training strategy, and can also be a complementary assessment tool to the written examinations and has better correlation with clinical performance.

Erythropoietin modulates macrophages but not post-ischemic acute kidney injury in mice.

BACKGROUND/PURPOSE: Substantial progress was made in acute kidney injury (AKI) over the past 10 years, but no therapeutic interventions have been shown to prevent AKI or accelerate functional recovery after injury. A large number of preclinical studies supports the use of recombinant human erythropoietin (rHuEPO) to prevent AKI, but the clinical trial data are inconclusive. To address concerns about preclinical study design and reporting in AKI, we here presented our rigorous experiments on the use of rHuEPO in a mouse model simulating the most common post-ischemic AKI in patients. METHODS: Use of saline vehicle or rHuEPO (100 or 1000 U/KgBW) in mice subjected to AKI induced by ischemia-reperfusion injury of left kidney 2 weeks after right nephrectomy (NX + IRI). RESULTS: NX + IRI resulted in a reproducible AKI model. Use of rHuEPO as a pretreatment or posttreatment did not affect AKI severity, functional recovery, and mouse survival regardless of gender, injury severity, or doses of rHuEPO. Administering rHuEPO with 1000 U/KgBW did increase hematocrit and modulate AKI kidney macrophages by Nos2 downregulation and Ccl17 upregulation. Active expression of erythropoietin receptor (EPOR) was not identified in renal cells by lineage tracing study, whereas expression of colony-stimulating factor 2 receptor ß (CSF2Rß) was identified in kidney macrophages and upregulated after AKI. Both EPOR and CSF2Rß were identified in cultured bone marrow derived macrophages, possibly mediated the robust inhibition of cytokine-induced phenotype switching by rHuEPO. CONCLUSION: Use of rHuEPO can modulate macrophage function but not the post-ischemic AKI severity, functional recovery and survival in mice.

Emergency department utilization and resuscitation rate among patients receiving maintenance hemodialysis.

BACKGROUND: End-stage renal disease (ESRD) is a growing global health concern with increased disease burden and high medical costs. Utilization of the emergency department (ED) among dialyzed patients and the associated risk factors remain unknown. METHODS: Participants of this study, selected from the National Health Insurance Database in Taiwan, were aged 19-90 years and received maintenance hemodialysis from January 1, 2010, to December 31, 2010. A control group consisting of individuals who did not receive dialysis, selected from the same data source, were matched for age, sex, and the Charlson Comorbidity Index (CCI). Subgroup analysis with hemodialysis frequency was also performed. ED utilization among enrolled individuals was assessed in 2012. Generalized estimating equations with multiple variable adjustments were used to identify risk factors associated with resuscitation during ED visits. RESULTS: One group of 2985 individuals who received maintenance hemodialysis, and another group of 2985 patients that did not receive hemodialysis, between January 1, 2010, and December 31, 2010, were included in this study. There were 4822 ED visits in the hemodialysis group, and 1755 ED visits in the non-dialysis group between January 1, 2012, and December 31, 2012. Analysis of multivariable generalized estimating equations identified the risk associated with resuscitation during ED visits to be greater in individuals who were receiving maintenance hemodialysis, aged older than 55 years, hospitalized in the past year, and assigned first and second degree of triage. CONCLUSION: Patients receiving maintenance hemodialysis had higher ED utilization and a significantly higher risk of resuscitation during ED visits than those without hemodialysis.

Urinary biomarkers predict advanced acute kidney injury after cardiovascular surgery.

BACKGROUND: Acute kidney injury (AKI) after cardiovascular surgery is a serious complication. Little is known about the ability of novel biomarkers in combination with clinical risk scores for prediction of advanced AKI. METHODS: In this prospectively conducted multicenter study, urine samples were collected from 149 adults at 0, 3, 6, 12 and 24 h after cardiovascular surgery. We measured urinary hemojuvelin (uHJV), kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL), α-glutathione S-transferase (uα-GST) and π-glutathione S-transferase (uπ-GST). The primary outcome was advanced AKI, under the definition of Kidney Disease: Improving Global Outcomes (KDIGO) stage 2, 3 and composite outcomes were KDIGO stage 2, 3 or 90-day mortality after hospital discharge. RESULTS: Patients with advanced AKI had significantly higher levels of uHJV and uKIM-1 at 3, 6 and 12 h after surgery. When normalized by urinary creatinine level, uKIM-1 in combination with uHJV at 3 h post-surgery had a high predictive ability for advanced AKI and composite outcome (AUC = 0.898 and 0.905, respectively). The combination of this biomarker panel (normalized uKIM-1, uHJV at 3 h post-operation) and Liano's score was superior in predicting advanced AKI (AUC = 0.931, category-free net reclassification improvement of 1.149, and p <  0.001). CONCLUSIONS: When added to Liano's score, normalized uHJV and uKIM-1 levels at 3 h after cardiovascular surgery enhanced the identification of patients at higher risk of progression to advanced AKI and composite outcomes.

Role of renin-angiotensin system in acute kidney injury-chronic kidney disease transition.

Acute kidney injury (AKI) can increase the risk of developing incident chronic kidney disease (CKD). The severity, frequency and duration of AKI are crucial predictors of poor renal outcome. A repair process after AKI can be adaptive and kidney recovers completely after a mild injury. However, severe injury will lead to a maladaptive repair, which frequently progresses to nephron loss, vascular rarefaction, chronic inflammation and fibrosis. Although different mechanisms underlying AKI-CKD transition have been extensively discussed, no definite intervention has been proved effective to block or to retard the transition until recently. In CKD, renin-angiotensin system (RAS) inhibitor has been proved effective to slow down disease progression. Furthermore, RAS needs to be highlighted again in AKI-CKD transition because recent animal studies have shown the activation of intra-renal RAS after AKI, and RAS blockade can reduce the ensuing CKD and mortality. In patients with the complete renal recovery after AKI, administration of RAS inhibitor is associated with reduced risk of subsequent CKD as well. In this article, we will demonstrate the role of RAS in AKI-CKD transition comprehensively. We will then emphasize the promising effect of RAS inhibitor on CKD prevention in patients recovering from AKI based on evidence from the bench to clinical research. All of these discussions will contribute to the establishment of reliable monitoring and therapeutic strategies for patients with functional recovery from AKI who can be most easily ignored.

Update of pathophysiology and management of diabetic kidney disease.

Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in patients with diabetes mellitus and the leading cause of end-stage renal disease in the world. The most characteristic marker of DKD is albuminuria, which is associated with renal disease progression and cardiovascular events. Renal hemodynamics changes, oxidative stress, inflammation, hypoxia and overactive renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis of DKD, and renal fibrosis plays the key role. Intensified multifactorial interventions, including RAAS blockades, blood pressure and glucose control, and quitting smoking, help to prevent DKD development and progression. In recent years, novel agents are applied for preventing DKD development and progression, including new types of glucose-lowering agents, pentoxifylline, vitamin D analog paricalcitol, pyridoxamine, ruboxistaurin, soludexide, Janus kinase inhibitors and nonsteroidal minerocorticoid receptor antagonists. In this review, recent large studies about DKD are also summarized.

Novel insights into acute kidney injury-chronic kidney disease continuum and the role of renin-angiotensin system.

Acute kidney injury (AKI) is an independent risk factor for chronic kidney disease (CKD). If injury is mild, a repair process can be adaptive and lead to complete renal recovery. However, severe injury will be accompanied by a maladaptive repair which usually leads to nephron loss, fibrosis, vascular rarefaction, and chronic inflammation. Although various mechanisms underlying AKI-CKD transition have been explored, no intervention has been proved effective to block the transition until very recently. A lack of consensus for monitoring renal function and defining renal recovery after AKI should be the reasons for the slow advance in the discovery of a timely pharmacologic treatment to block AKI-CKD transition. Recently, animal studies have shown the activation of renin-angiotensin system (RAS) after AKI. In patients with complete renal recovery after AKI defined as the decrease of serum creatinine level to within 0.3 mg/dL above the baseline, administration of RAS inhibitor can prevent the ensuing CKD. In this review, we will discuss the renal recovery after AKI and the mechanisms underlying AKI-CKD transition. We will then highlight the promising effect of RAS inhibitor on CKD prevention in patients with complete renal recovery from AKI based on the recent clinical evidence.