Akt1 is involved in renal fibrosis and tubular apoptosis in a murine model of acute kidney injury-to-chronic kidney disease transition.

Maladaptive repair after acute kidney injury (AKI) can predispose patients to chronic kidney disease (CKD). However, the molecular mechanism underlying the AKI-to-CKD transition remains unclear. The Akt signaling pathway has been reported to be involved in the pathological processes of both AKI and CKD. In this study, we investigated the role of Akt1 in a murine model of the AKI-to-CKD transition. Wild-type (WT) and Akt1-/- mice were subjected to unilateral ischemia-reperfusion injury (UIRI), with their kidneys harvested after two days and two, four, and six weeks after UIRI. The dynamic changes in tubulointerstitial fibrosis, markers of tubular epithelial-mesenchymal transition (EMT), and tubular apoptosis were investigated. Akt1 of the three Akt isoforms was activated during the AKI-to-CKD transition. After UIRI, tubulointerstitial fibrosis and tubular EMT were significantly increased in WT mice, but were attenuated in Akt1-/- mice. The expression of the transforming growth factor (TGF)-ß1/Smad was increased in both WT and Akt1-/- mice, but was not different between the two groups. The levels of phosphorylated glycogen synthase kinase (GSK)-3ß, Snail, and ß-catenin in the Akt1-/- mice were lower than those in the WT mice. The number of apoptotic tubular cells and the expression of cleaved caspase-3/Bax were both lower in Akt1-/- mice than in WT mice. Genetic deletion of Akt1 was associated with attenuation of tubulointerstitial fibrosis, tubular EMT, and tubular apoptosis during the AKI-to-CKD transition. These findings were associated with TGF-ß1/Akt1/GSK-3ß/(Snail and ß-catenin) signaling independent of TGF-ß1/Smad signaling. Thus, Akt1 signaling could serve as a potential therapeutic target for inhibiting the AKI-to-CKD transition.

Clinical implications of changes in metabolic syndrome status after kidney transplantation: a nationwide prospective cohort study.

BACKGROUND: Metabolic syndrome (MetS) is prevalent in patients with end-stage kidney disease, and kidney transplantation is expected to modify the metabolic status. However, whether changes in metabolic status at the time of transplantation affect recipient outcomes remains unclear. METHODS: We analyzed 4187 recipients registered in a nationwide prospective cohort from 2014 to 2020. MetS was defined as the presence of three or more components of the metabolic syndrome. Patients were classified based on the pre- and post-transplant MetS status: MetS-free, MetS-developed, MetS-recovered and MetS-persistent. Study outcomes were occurrence of death-censored graft loss and a composite of cardiovascular events and death. RESULTS: Among recipients without pre-transplant MetS, 19.6% (419/2135) developed post-transplant MetS, and MetS disappeared in 38.7% (794/2052) of the recipients with pre-transplant MetS. Among the four groups, the MetS-developed group showed the worst graft survival rate, and the MetS-persistent group had a poorer composite event-free survival rate. Compared with the MetS-free group, the MetS-developed group was associated with an increased risk of graft loss [adjusted hazard ratio (aHR) 2.35; 95% confidence interval (CI) 1.17-4.98] and the risk of graft loss increased with increasing numbers of dysfunctional MetS components. MetS-persistent was associated with increased risks of cardiovascular events and death (aHR 2.46; 95% CI 1.12-5.63), but changes in the number of dysfunctional MetS components was not. CONCLUSION: Kidney transplantation significantly alters the metabolic status. Newly developed MetS after transplantation was associated with an increased risk of graft loss, whereas persistent MetS exposure before and after transplantation was associated with increased risks cardiovascular events and patient survival.

Effect of low-density lipoprotein level and mortality in older incident statin-naïve hemodialysis patients.

BACKGROUND: This study aimed to analyze low-density lipoprotein cholesterol (LDL-C) levels and their relationship with mortality in order to identify the appropriate lipid profile for older Korean hemodialysis patients. METHODS: We enrolled a total of 2,732 incident hemodialysis patients aged > 70 years from a retrospective cohort of the Korean Society of Geriatric Nephrology from 2010 Jan to 2017 Dec, which included 17 academic hospitals in South Korea. Of these patients, 1,709 were statin-naïve, and 1,014 were analyzed after excluding those with missing LDL-C level data. We used multivariate Cox regression analysis to select risk factors from 20 clinical variables among the LDL-C groups. RESULTS: The mean age of the entire patient population was 78 years, with no significant differences in age between quartiles Q1 to Q4. However, the proportion of males decreased as the quartiles progressed towards Q4 (p < 0.001). The multivariate Cox regression analysis, which included all participants, showed that low LDL-C levels were associated with all-cause mortality. In the final model, compared to Q1, the hazard ratios (95% confidence interval) were 0.77 (0.620-0.972; p = 0.027), 0.85 (0.676-1.069; p = 0.166), and 0.65 (0.519-0.824; p < 0.001) for Q2, Q3, and Q4, respectively, after adjusting for covariates, such as conventional and age-specific risk factors. The final model demonstrated that all-cause mortality increased as LDL-C levels decreased, as confirmed by a restrictive cubic spline plot. CONCLUSIONS: In older hemodialysis patients who had not previously received dyslipidemia treatment, elevated LDL-C levels were not associated with increased all-cause mortality. Intriguingly, lower LDL-C levels appear to be associated with an unfavorable effect on all-cause mortality among high-risk hemodialysis patients.

Regulation of Epithelial-Mesenchymal Transition of A549 Cells by Prostaglandin D2.

BACKGROUND/AIMS: Despite significant advances in diagnostic and operative techniques, lung cancer remains one of the most lethal malignancies worldwide. Since prostaglandins such as prostaglandin D2 (PGD2) is involved in various pathophysiological process, including inflammation and tumorigenesis, this study aims to investigate the role of PGD2 during the process of epithelial-mesenchymal transition (EMT) in A549 cells. METHODS: A549 cells were stimulated with PGD2 and expression of EMT markers was analyzed by immunoblotting and immunofluorescence. EMT-related gene, Slug expression was evaluated using quantitative real-time polymerase chain reaction (qPCR). Migration and invasion abilities of A549 cells were determined in chemotaxis and Matrigel invasion assays, respectively. We also inhibited the TGF/Smad signaling pathway using a receptor inhibitor or silencing of TGF-ß1 and TGFß type I receptor (TGFßRI), and protein expression was assessed by immunoblotting and immunofluorescence. RESULTS: Here, we found that stimulation of A549 cells with PGD2 resulted in morphological changes into a mesenchymal-like phenotype under low serum conditions. Stimulation of A549 cells with PGD2 resulted in a significant reduction in proliferation, whereas invasion and migration were enhanced. The expression of E-cadherin was markedly downregulated, while Vimentin expression was upregulated after treatment of A549 cells with PGD2. Slug expression was markedly upregulated by stimulating A549 cells with PGD2, and stimulation of A549 cells with PGD2 significantly enhanced TGF-ß1 expression, and silencing of TGF-ß1 significantly blocked PGD2-induced EMT and Smad2 phosphorylation. In addition, PGD2-induced Smad2 phosphorylation and EMT were significantly abrogated by either pharmacological inhibition or silencing of TGFßRI. PGD2-induced expression of Slug and EMT were significantly augmented in low nutrient and low serum conditions. Finally, the subsequent culture of mesenchymal type of A549 cells under normal culture conditions reverted the cell's phenotype to an epithelial type. CONCLUSION: Given these results, we suggest that tumor microenvironmental factors such as PGD2, nutrition, and growth factors could be possible therapeutic targets for treating metastatic cancers.

Association between physical activity and risk of renal function decline and mortality in community-dwelling older adults: a nationwide population-based cohort study.

BACKGROUND: Physical activity (PA) is an important risk factor associated with health outcomes. However, the relationship between PA and kidney function decline in older adults remains unclear. We examined the influence of PA on kidney function decline and mortality in community-dwelling older adults. METHODS: Adults aged ≥ 65 years with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 who had available health checkup data from 2009 to 2010 were included. The cohort was followed annually through December 2015 for anthropometric, sociodemographic, and medical information including outcomes and biennially for laboratory information from the health checkup. We divided these patients into three groups according to self-reported PA (Inactive group: no leisure-time PA, Active group: vigorous activity for at least 80 min/week or a sum of moderate-intensity activity and walking for at least 300 min/week, Low-active group: level of PA between the definitions of the other two groups). Associations between the intensity of PA and death, cardiovascular death, and ≥ 50% eGFR decline were investigated. RESULTS: Among 102,353 subjects, 32,984 (32.23%), 54,267 (53.02%), and 15,102 (14.75%) were classified into the inactive, low-active, and active groups, respectively. The active group was younger, contained a higher proportion of men, and had higher frequencies of hypertension, diabetes mellitus, drinking, and smoking than the other groups. The active group had significantly lower incidence rates of mortality, cardiovascular mortality, and kidney function decline than the other groups (all p < 0.001). The active group also showed lower all-cause (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.70-0.82) and cardiovascular mortality (HR, 0.64; 95% CI, 0.53-0.78) and protection against ≥ 50% eGFR decline (HR, 0.81; 95% CI, 0.68-0.97) compared with the inactive group in the fully adjusted Cox proportional hazards regression model. CONCLUSIONS: High PA was an independent modifiable lifestyle factor for reducing mortality and protecting against declines in kidney function in older adults.

Maintenance of the critical care system during the pandemic in non-COVID-19 patients requiring continuous renal replacement therapy: a single center experience.

BACKGROUND: During the COVID-19 pandemic, maintenance of essential healthcare systems became very challenging. We describe the triage system of our institute, and assess the quality of care provided to critically ill non-COVID-19 patients requiring continuous renal replacement therapy (CRRT) during the pandemic. METHODS: We introduced an emergency triage pathway early in the pandemic. We retrospectively reviewed the medical records of patients who received CRRT in our hospital from January 2016 to March 2021. We excluded end-stage kidney disease patients on maintenance dialysis. Patients were stratified as medical and surgical patients. The time from hospital arrival to intensive care unit (ICU) admission, the time from hospital arrival to intervention/operation, and the in-hospital mortality rate were compared before (January 2016 to December 2019) and during (January 2021 to March 2021) the pandemic. RESULTS: The mean number of critically ill patients who received CRRT annually in the surgical department significantly decreased during the pandemic in (2016-2019: 76.5 ± 3.1; 2020: 56; p < 0.010). Age, sex, and the severity of disease at admission did not change, whereas the proportions of medical patients with diabetes (before: 44.4%; after: 56.5; p < 0.005) and cancer (before: 19.4%; after: 32.3%; p < 0.001) increased during the pandemic. The time from hospital arrival to ICU admission and the time from hospital arrival to intervention/operation did not change. During the pandemic, 59.6% of surgical patients received interventions/operations within 6 hours of hospital arrival. In Cox's proportional hazard modeling, the hazard ratio associated with the pandemic was 1.002 (0.778-1.292) for medical patients and 1.178 (0.783-1.772) for surgical patients. CONCLUSION: Our triage system maintained the care required by critically ill non-COVID-19 patients undergoing CRRT at our institution.

Assessment of Hindfoot Alignment: Intraoperative Fluoroscopy Versus Standing Radiograph.

Few intraoperative assessments are available for hindfoot alignment. In the current study, we demonstrated the feasibility of hindfoot alignment via intraoperative fluoroscopy. We retrospectively compared measurements of heel alignment obtained via intraoperative fluoroscopy with those acquired using standard radiographs. Two observers compared the heel alignment ratios and angles derived from 100 pairs of images. The effects of age, sex, laterality, and body mass index on the discrepancy between fluoroscopic images and radiographs were analyzed. The heel alignment ratio revealed a strong correlation between standing radiograph and intraoperative fluoroscopy, based on a correlation coefficient of 0.844 (p < .001). The heel alignment angle also showed significant correlation based on a correlation coefficient value of 0.667 (p < .001). None of the demographic factors showed any significant effect on the discrepancy between the 2 sets of images. Our study showed that the heel alignment determined via intraoperative fluoroscopy was comparable to that of a standard standing radiograph without any significant association with demographic factors.

Intradialytic Hypotension and Newly Recognized Peripheral Artery Disease in Patients Receiving Hemodialysis.

RATIONALE & OBJECTIVE: Intradialytic hypotension (IDH) may decrease systemic circulation to the legs, exacerbating symptoms of peripheral artery disease (PAD). We sought to evaluate the relationship between IDH and newly recognized lower extremity PAD among hemodialysis patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Linking data from the US Renal Data System to the electronic health records of a large dialysis provider, we identified adult patients (≥18 years of age) with Medicare Parts A and B who initiated dialysis (2006-2011) without previously recognized PAD. EXPOSURE: The time-varying proportion of hemodialysis sessions with IDH defined as the nadir intradialytic systolic blood pressure <90 mm Hg. We categorized the proportion of sessions with IDH within serial 30-day intervals as 0%, >0% to <15%, 15% to <30%, and ≥30%. OUTCOMES: Newly recognized PAD was ascertained using PAD diagnostic and procedure codes for amputation or revascularization, in serial 30-day intervals subsequent to each 30-day exposure interval. ANALYTICAL APPROACH: To account for the competing risks of death and kidney transplantation, we estimated unadjusted and adjusted subdistribution hazard ratios using the Kaplan-Meier multiple imputation method in combination with the extended Cox model to account for IDH as a time-varying exposure. RESULTS: Among 45,591 patients, those with more frequent baseline IDH had a higher prevalence of cardiovascular diseases. During 61,725 person-years of follow-up, 7,886 patients had newly recognized PAD. We found a graded, direct association between IDH and newly recognized PAD. For example, having IDH in ≥30% of dialysis sessions during a given 30-day interval (vs 0%) was associated with a 24% (95% CI, 17%-32%) higher hazard than having newly recognized PAD in the subsequent 30 days. LIMITATIONS: Unmeasured confounding; ascertainment of PAD from claims. CONCLUSIONS: Patients receiving hemodialysis who had more frequent IDH had higher rates of newly recognized PAD. Patients with frequent IDH may warrant careful examination for PAD.

Akt1 is involved in tubular apoptosis and inflammatory response during renal ischemia-reperfusion injury.

Renal ischemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI). Although Akt is involved in renal IRI, it is unclear as to which Akt isoform plays an important role in renal IRI. In this study, we investigated the role of Akt1 in renal IRI. We subjected the C57BL/6 male mice to unilateral IRI with contralateral nephrectomy. Two days after IRI, IRI-kidneys were harvested. The mice were divided into four groups: wild type (WT) IRI, Akt1-/- IRI, WT sham, and Akt1-/- sham. We found that Akt1, not Akt2 or Akt3, was markedly activated in WT IRI than in WT sham mice. The histologic damage score and serum creatinine level significantly increased in WT IRI mice, the increase being the highest in Akt1-/- IRI mice. The number of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells and expression of cleaved caspase-3/Bax were higher in Akt1-/- IRI mice than in WT IRI mice. The expression of Bcl-2 was lower in Akt1-/- IRI mice than in WT IRI mice. The expression of tumor necrosis factor-α/interleukin-6/interleukin-1ß and number of F4/80-positive macrophages were markedly higher in Akt1-/- IRI than in WT IRI mice. The expression of phosphorylated nuclear factor-κB p65 was also higher in Akt1-/- IRI mice than in WT IRI mice. Our results show that Akt1 deletion exacerbates kidney damage as it increases tubular apoptosis and inflammatory response during renal IRI. Akt1 could be a potential therapeutic target for developing treatments against IRI-induced AKI.

RNA-Seq identifies condition-specific biological signatures of ischemia-reperfusion injury in the human kidney.

BACKGROUND: Acute kidney injury (AKI) is defined as a sudden event of kidney failure or kidney damage within a short period. Ischemia-reperfusion injury (IRI) is a critical factor associated with severe AKI and end-stage kidney disease (ESKD). However, the biological mechanisms underlying ischemia and reperfusion are incompletely understood, owing to the complexity of these pathophysiological processes. We aimed to investigate the key biological pathways individually affected by ischemia and reperfusion at the transcriptome level. RESULTS: We analyzed the steady-state gene expression pattern of human kidney tissues from normal (pre-ischemia), ischemia, and reperfusion conditions using RNA-sequencing. Conventional differential expression and self-organizing map (SOM) clustering analyses followed by pathway analysis were performed. Differential expression analysis revealed the metabolic pathways dysregulated in ischemia. Cellular assembly, development and migration, and immune response-related pathways were dysregulated in reperfusion. SOM clustering analysis highlighted the ischemia-mediated significant dysregulation in metabolism, apoptosis, and fibrosis-related pathways, while cell growth, migration, and immune response-related pathways were highly dysregulated by reperfusion after ischemia. The expression of pro-apoptotic genes and death receptors was downregulated during ischemia, indicating the existence of a protective mechanism against ischemic injury. Reperfusion induced alterations in the expression of the genes associated with immune response such as inflammasome and antigen representing genes. Further, the genes related to cell growth and migration, such as AKT, KRAS, and those related to Rho signaling, were downregulated, suggestive of injury responses during reperfusion. Semaphorin 4D and plexin B1 levels were also downregulated. CONCLUSIONS: We show that specific biological pathways were distinctively involved in ischemia and reperfusion during IRI, indicating that condition-specific therapeutic strategies may be imperative to prevent severe kidney damage after IRI in the clinical setting.

Differential Urinary Proteome Analysis for Predicting Prognosis in Type 2 Diabetes Patients with and without Renal Dysfunction.

Renal dysfunction, a major complication of type 2 diabetes, can be predicted from estimated glomerular filtration rate (eGFR) and protein markers such as albumin concentration. Urinary protein biomarkers may be used to monitor or predict patient status. Urine samples were selected from patients enrolled in the retrospective diabetic kidney disease (DKD) study, including 35 with good and 19 with poor prognosis. After removal of albumin and immunoglobulin, the remaining proteins were reduced, alkylated, digested, and analyzed qualitatively and quantitatively with a nano LC-MS platform. Each protein was identified, and its concentration normalized to that of creatinine. A prognostic model of DKD was formulated based on the adjusted quantities of each protein in the two groups. Of 1296 proteins identified in the 54 urine samples, 66 were differentially abundant in the two groups (area under the curve (AUC): p-value < 0.05), but none showed significantly better performance than albumin. To improve the predictive power by multivariate analysis, five proteins (ACP2, CTSA, GM2A, MUC1, and SPARCL1) were selected as significant by an AUC-based random forest method. The application of two classifiers-support vector machine and random forest-showed that the multivariate model performed better than univariate analysis of mucin-1 (AUC: 0.935 vs. 0.791) and albumin (AUC: 1.0 vs. 0.722). The urinary proteome can reflect kidney function directly and can predict the prognosis of patients with chronic kidney dysfunction. Classification based on five urinary proteins may better predict the prognosis of DKD patients than urinary albumin concentration or eGFR.

Reoperation rate, mortality and ambulatory ability after internal fixation versus hemiarthroplasty for unstable intertrochanteric fractures in elderly patients: a study on Korean Hip Fracture Registry.

INTRODUCTION: The treatment of unstable intertrochanteric fracture in elderly patients is challenging and how to treat these patients remains controversial. The purposes of this study were to compare (1) reoperation rate, (2) mortality and (3) the postoperative change of walking ability between patients undergoing internal fixation (IF) and those undergoing bipolar hemiarthroplasty (HA) due to this type of fracture based on the data from the Korean Hip Fracture Registry. MATERIALS AND METHODS: Between July 2014 and June 2016, we extracted 623 unstable intertrochanteric fractures (616 patients aged ≥ 65 years) according to the classification of the Association for the Study of Internal Fixation-American Orthopaedic Trauma Association. Among the 564 patients, 396 were treated with IF (IF group) and 168 with bipolar HA (HA group). We compared the reoperation rate and mortality between IF group and HA group. In patients, who were followed up more than 2 years after the surgery, we compared the postoperative change of walking activity from ambulatory outdoors (Koval's grade 1, 2, 3) to housebound (Koval's grade 4, 5, 6). RESULTS: The rate of reoperation was higher in the IF group (24/396, 6.1%) than in the HA (4/168, 2.4%) (p = 0.046). At the final follow-up, 79 (35.7%) of the 221 IF patients became housebound, whereas 21 (23.3%) of the 90 HA patients became housebound (p = 0.022). CONCLUSION: This study showed HA was associated with lower rate of reoperation and lower decrement rate of walking ability compared to IF in elderly patients with unstable intertrochanteric fractures.

Is subtle cavus foot a risk factor for chronic ankle instability? Comparison of prevalence of subtle cavus foot between chronic ankle instability and control group on the standing lateral radiograph.

BACKGROUND: Subtle cavus foot (SCF) is an entity characterized by mild cavus. However, few studies have examined whether a SCF may be a risk factor for chronic ankle instability (CAI). METHODS: This study included 116 patients who underwent lateral ankle ligament repair (modified Broström operation) for CAI and 105 controls. We used the standing lateral radiograph, so compared calcaneal pitch angle, Meary's angle, heights of the first and fifth metatarsal bases, and fibular positions between groups. Additionally, two observers subjectively rated the standing lateral radiographs for the presence of SCF. RESULTS: There were no significant intergroup differences in any of the radiographic angles. The prevalence of SCF was 20.7% in the CAI group and 18.1% in the control group according to observer 1 versus 21.6% and 28.6% (CAI group and control group, respectively) according to observer 2. There were no significant intergroup differences in the proportion of SCF between the two observers (p=0.105 and 0.211, respectively). CONCLUSION: SCF was not a significant risk factor for CAI when judging by standing lateral radiograph, and the detection of SCF seems to require considerable experience. Thus, care should be taken when determining whether to perform corrective osteotomies when treating CAI patients with SCF. LEVEL OF EVIDENCE: III, case control.

Plasma neutrophil gelatinase-associated lipocalin is associated with iron status in anemic patients with pre-dialysis chronic kidney disease.

BACKGROUND: Iron deficiency anemia is common in patients with chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of acute kidney injury, is known to be associated with iron metabolism. We investigated whether plasma NGAL level is associated with iron status in pre-dialysis CKD patients with anemia. METHODS: This study included 419 patients who had anemia. The subjects were into categorized into a pre-dialysis group (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2, n = 288) and a non-CKD group (eGFR >60 ml/min/1.73 m2, n = 131). The associations between plasma NGAL and iron status (serum ferritin and transferrin saturation [TSAT]), eGFR, albumin, uric acid, total cholesterol, calcium, phosphate, and C-reactive protein (CRP) were assessed. RESULTS: In non-CKD group, plasma NGAL was not associated with any baseline variables including iron indices (TSAT and serum ferritin). In pre-dialysis group, univariate analysis showed plasma NGAL correlated with eGFR, CRP, TSAT, and serum ferritin. In multivariate analysis, plasma NGAL was independently associated with TSAT. However, serum ferritin lost its association with plasma NGAL. In ROC analysis for identifying iron deficiency, the plasma NGAL (best cut-off value ≤394 ng/ml) was superior to the serum ferritin (suggested cut-off value ≤500 ng/ml) in both sensitivity and specificity. CONCLUSIONS: Plasma NGAL is associated with iron status in anemic patients with pre-dialysis CKD. Further studies are needed to demonstrate the role of plasma NGAL in assessing the iron deficiency and in guiding the iron therapy for pre-dialysis CKD patients.

Long-term outcomes in acute kidney injury patients who underwent continuous renal replacement therapy: a single-center experience.

INTRODUCTION: Acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) is the most severe form of AKI associated with poor short- and long-term patient outcomes. The aim of this study was to evaluate the variables associated with long-term patient survival in our clinic. METHODS: This was a single-center retrospective study with AKI survivors who received CRRT from March 2011 to February 2015. During the study period, all consecutive AKI survivors who underwent CRRT were included. Patients on maintenance dialysis prior to CRRT were excluded. Data were collected by reviewing the patients' medical charts. Long-term follow-up data were gathered through February 2018. RESULTS: A total of 430 patients were included, and 62.8% of the patients were male. The mean age of the patients was 63.4 ± 14.6 years. The mean serum creatinine level at the time of CRRT initiation was 3.5 ± 2.5 mg/dL. At the time of discharge, the mean eGFR and serum creatinine levels were 58.4 ± 46.7 and 1.7 ± 1.6 mg/dL, respectively. After 3 years, 44.9% of the patients had survived. When we investigated the factors associated with long-term patient mortality, a longer stay in the ICU [OR 1.034 (1.016-1.053), p < 0.001], a history of cancer [OR 3.830 (1.037-3.308), p = 0.037], a prolonged prothrombin time [OR 1.852 (1.037-3.308), p = 0.037] and a lower eGFR at the time of discharge [OR 0.988 (0.982-0.995), p = 0.001] were independently associated with long-term patient mortality. CONCLUSION: Our study demonstrates that long-term mortality after CRRT is associated with longer ICU stays and lower eGFRs at the time of hospital discharge. Our data imply the importance of renal recovery for long-term survival of AKI patients treated with CRRT.

The two isoforms of matrix metalloproteinase- 2 have distinct renal spatial and temporal distributions in murine models of types 1 and 2 diabetes mellitus.

BACKGROUND: We recently reported on the enhanced tubular expression of two discrete isoforms of the MMP-2 (full length and N-terminal truncated, FL-MMP-2, NTT-MMP-2) in a murine model and human diabetic kidneys. In the present study, we examined in more detail the temporal and spatial distributions of MMP-2 isoform expression in murine models of Type 1 and Type 2 diabetes mellitus. METHODS: Diabetic models were streptozotocin (STZ)-induced diabetes (Type 1 diabetes mellitus) and db/db mice (Type 2 diabetes mellitus). We quantified the abundance of two isoforms of MMP-2 transcripts by qPCR. A spatial distribution of two isoforms of MMP-2 was analyzed semi-quantitatively according to time after injection of STZ and with increasing age of db/db mice. Furthermore, immunohistochemistry for nitrotyrosine was performed to examine a potential association between oxidative stress and MMP-2 isoform expression. RESULTS: Both isoforms of MMP-2 were upregulated in whole kidneys from STZ and db/db mice. In the case of FL-MMP-2, mRNA levels significantly increased at 12 and 24 weeks in STZ mice, while the isoform expression was significantly increased only at 16 weeks, in the db/db mice. FL-MMP-2 protein levels increased in the cortices and outer medullae of both STZ and db/db mice as a function of the duration of diabetes. For NTT-MMP-2, mRNA levels increased earlier at 4 weeks in STZ mice and at 10 weeks of age in db/db mice. The expression of NTT-MMP-2 also increased, primarily in the cortices of STZ and db/db mice, as a function of the duration of diabetes. Quantitatively, these findings were consistent with the qPCR results in the case of NTT-MMP-2, respectively (STZ 24 weeks, 3.24 ± 3.70 fold; 16 weeks db/db, 4.49 ± 0.55 fold). In addition, nitrotyrosine was expressed primarily in cortex as compared to medulla as a function of the duration of diabetes similar to NTT-MMP-2 expression. CONCLUSIONS: Two isoforms of MMP-2 are highly inducible in two diabetic murine models and become more abundant as a function of time. As the expression patterns were not the same in the two isoforms of MMP-2, it is possible that each isoform has a discrete role in the development of diabetic renal injury.

An intracellular matrix metalloproteinase-2 isoform induces tubular regulated necrosis: implications for acute kidney injury.

Acute kidney injury (AKI) causes severe morbidity, mortality, and chronic kidney disease (CKD). Mortality is particularly marked in the elderly and with preexisting CKD. Oxidative stress is a common theme in models of AKI induced by ischemia-reperfusion (I-R) injury. We recently characterized an intracellular isoform of matrix metalloproteinase-2 (MMP-2) induced by oxidative stress-mediated activation of an alternate promoter in the first intron of the MMP-2 gene. This generates an NH2-terminal truncated MMP-2 (NTT-MMP-2) isoform that is intracellular and associated with mitochondria. The NTT-MMP-2 isoform is expressed in kidneys of 14-mo-old mice and in a mouse model of coronary atherosclerosis and heart failure with CKD. We recently determined that NTT-MMP-2 is induced in human renal transplants with delayed graft function and correlated with tubular cell necrosis. To determine mechanism(s) of action, we generated proximal tubule cell-specific NTT-MMP-2 transgenic mice. Although morphologically normal at the light microscopic level at 4 mo, ultrastructural studies revealed foci of tubular epithelial cell necrosis, the mitochondrial permeability transition, and mitophagy. To determine whether NTT-MMP-2 expression enhances sensitivity to I-R injury, we performed unilateral I-R to induce mild tubular injury in wild-type mice. In contrast, expression of the NTT-MMP-2 isoform resulted in a dramatic increase in tubular cell necrosis, inflammation, and fibrosis. NTT-MMP-2 mice had enhanced expression of innate immunity genes and release of danger-associated molecular pattern molecules. We conclude that NTT-MMP-2 "primes" the kidney to enhanced susceptibility to I-R injury via induction of mitochondrial dysfunction. NTT-MMP-2 may be a novel AKI treatment target.

Urine clusterin/apolipoprotein J is linked to tubular damage and renal outcomes in patients with type 2 diabetes mellitus.

OBJECTIVE: The objective of this study was to evaluate the association of urine clusterin/apolipoprotein J (Apo J) with the development and/or progression of diabetic kidney disease (DKD) in type 2 diabetes. MATERIALS AND METHODS: A total of 159 type 2 diabetic patients and 20 nondiabetic subjects with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 were enrolled. The baseline values of urine clusterin and tubular damage markers were measured. The primary outcome was the annual decline rate in eGFR, and secondary outcomes were the development of chronic kidney disease (CKD) stage 3 or greater and the persistence/progression of albuminuria. The median follow-up duration of enrolled patients was 3.0 (1.0-5.9) years. RESULTS: Baseline clusterin levels in urine were significantly increased in type 2 diabetic subjects compared with those of nondiabetic subjects. The levels of urine clusterin had a significant correlation with urine tubular damage markers. A positive correlation between the annual rate of decline in eGFR and urine clusterin after adjusting for clinical confounding factors was detected. Multivariate analysis further indicated that urine clusterin correlated with the development of CKD stage 3 or greater and persistence/progression of albuminuria. In type 2 diabetic subjects with albuminuria, urine clusterin remained associated with the annual decline rate in eGFR and the progression of CKD stage. CONCLUSIONS: Urine clusterin reflects tubular damage in the early stage of DKD. The increase in urine clusterin along with albuminuria could be an independent predictive marker for the progression of DKD in type 2 diabetes.

The role of the specialized team in the operation of continuous renal replacement therapy: a single-center experience.

BACKGROUND: The requirement of continuous renal replacement therapy (CRRT) is increasing with the growing incidence of acute kidney injury (AKI). The decision to initiate CRRT is not difficult if an adequate medical history is obtained. However, the handling and maintenance of CRRT constitute a labor-intensive intervention that requires specialized skills. For these reasons, our center organized a specialized CRRT team in March 2013. The aim of this study is to report on the role of a specialized CRRT team and to evaluate the team's outcome. METHODS: This retrospective single-center study evaluated AKI patients who underwent CRRT in the intensive care unit (ICU) from March 2011 to February 2015. Patients were divided into two groups based on whether they received specialized CRRT team intervention. We collected information on demographic characteristics, laboratory parameters, SOFA score, CRRT initiation time, actual delivered dose and CRRT down-time. In-hospital mortality was defined by medical chart review. Binary logistic regression analysis was used to define factors associated with in-hospital mortality. RESULTS: A total of 1104 patients were included in this study. The mean patient age was 63.85 ± 14.39 years old, and 62.8% of the patients were male. After the specialized CRRT team intervention, there was a significant reduction in CRRT initiation time (5.30 ± 13.86 vs. 3.60 ± 11.59 days, p = 0.027) and CRRT down-time (1.78 ± 2.23 vs. 1.38 ± 2.08 h/day, p = 0.002). The rate of in-hospital mortality decreased after the specialized CRRT team intervention (57.5 vs. 49.2%, p = 0.007). When the multivariable analysis was adjusted, delayed CRRT initiation (HR 1.054(1.036-1.072), p < 0.001) was a significant factor in predicting in-hospital mortality, along with an increased SOFA score, lower serum albumin and prolonged prothrombin time. CONCLUSIONS: Our study shows that specialized CRRT team intervention reduced CRRT initiation time, down-time and in-hospital mortality. This study could serve as a logical basis for implementing specialized CRRT teams hospital-wide.

Changes in Urinary Angiotensinogen Associated with Deterioration of Kidney Function in Patients with Type 2 Diabetes Mellitus.

Urinary angiotensinogen (AGT) is potentially a specific biomarker for the status of the intrarenal renin-angiotensin system (RAS) in patients with diabetes mellitus. We explored whether changes in urinary AGT excretion levels were associated with the deterioration of kidney function in type 2 diabetes patients with preserved kidney function. Urinary baseline AGT levels were measured in 118 type 2 diabetic patients who were not taking RAS blockers and who had estimated glomerular filtration rates (eGFRs) ≥ 60 mL/min/1.73 m². A total of 91 patients were followed-up for 52 months. Changes in urinary levels of AGT (ΔAGT) were calculated by subtracting urinary AGT/creatinine (Cr) at baseline from urinary AGT/Cr after 1 year. ΔAGT was significantly inversely correlated with annual eGFR change (ß = -0.29, P = 0.006; ß = -0.37, P = 0.001 after adjusting for clinical factors). RAS blockers were prescribed in 36.3% of patients (n = 33) during follow-up. The ΔAGT values were lower in the RAS blockers users than in the non-RAS blockers users, but the differences were not statistically significant (7.37 ± 75.88 vs. 22.55 ± 57.45 µg/g Cr, P = 0.081). The ΔAGT values remained significantly correlated with the annual rate of eGFR change (ß = -0.41, P = 0.001) in the patients who did not use RAS blockers, but no such correlation was evident in the patients who did. ΔAGT is inversely correlated with annual changes in eGFR in type 2 diabetes patients with preserved kidney function, particularly in RAS blocker-naïve patients.