Knockout of the C3a receptor protects against renal ischemia reperfusion injury by reduction of NETs formation.

Renal ischemia/reperfusion (I/R) injury is a local sterile inflammatory response driven by innate immunity. Emerging data have revealed that complement and neutrophils contribute to hyperinflammation and oxidative stress in I/R induced acute kidney injury (AKI). However, the interplay between the C3a/C3aR axis and neutrophil extracellular traps (NETs) is imcompletelyunderstood. Here, we utilize genetically engineered mouse models and pharmacological inhibitors to investigate this association. The C3a/C3aR axis is found to promote neutrophil recruitment and NETs formation, thereby accelerating renal damage and dysfunction. Knockout of C3aR restores NETs release and improves renal function after I/R injury. Antibody-mediated blockade of NETs can also significantly ameliorate renal tubular injury and inflammation. Consistently, under stimulation by C3a, neutrophils are activated to promote NETs formation and subsequent renal tubular epithelial cell damage, and blocking C3aR rescued the injury. Interfering with reactive oxygen species (ROS) accumulation in neutrophils by antioxidant treatment significantly attenuates NETs formation. Our findings demonstrate that the C3a/C3aR-ROS-NETs axis constitutes a promising target for prevention or treatment of renal I/R injury.

sPLA2-IB and PLA2R mediate insufficient autophagy and contribute to podocyte injury in idiopathic membranous nephropathy by activation of the p38MAPK/mTOR/ULK1ser757 signaling pathway.

Secretory phospholipase A2 group IB (sPLA2-IB) and M-type phospholipase A2 receptor (PLA2R) are closely associated with proteinuria in idiopathic membranous nephropathy (IMN). Podocytes constitute an important component of glomerular filtration, and high basal autophagy is indispensable for podocyte function. The current study aimed to analyze the relationship between sPLA2-IB and podocyte autophagy in IMN and determine whether sPLA2-IB mediates abnormal autophagy regulation in podocytes. The serum sPLA2-IB level and podocyte autophagy were detected, and clinical data were collected from IMN patients with different proteinuria levels. Then, the effects of sPLA2-IB on autophagy signaling pathways were evaluated in cultured human podocytes treated with sPLA2-IB, rapamycin, p38 inhibition, and PLA2R-siRNA in vitro. We found that IMN patients with nephrotic-range proteinuria have a significantly higher level of sPLA2-IB and fewer autophagosomes than those with non-nephrotic-range proteinuria. In vitro sPLA2-IB-induced insufficient autophagy in podocytes and promoted podocyte injury via activation of the mTOR/ULK1ser757 signaling pathway. Moreover, inhibition of p38 MAPK evidently abrogated sPLA2-IB-induced autophagy and the activation of mTOR/ULK1ser757 . Additionally, PLA2R silencing demonstrated that sPLA2-IB-induced abnormal autophagy was also PLA2R-dependent. In conclusion, the results revealed that sPLA2-IB downregulated autophagy and contributed to podocyte injury via PLA2R though activation of the p38MAPK/mTOR/ULK1ser757 signaling pathway.

Impact of donation after circulatory death donor allografts on outcomes following liver transplantation for fulminant hepatic failure in the United States.

Limited data exist regarding the impact of donation after circulatory death (DCD) allografts on outcomes following liver transplantation in fulminant hepatic failure (FHF). Utilizing the Scientific Registry of Transplant Recipients (SRTR), we compared outcomes after DCD in FHF to donation after brain death (DBD) in FHF and DCD in non-FHF over a 15-year period. Primary outcome measures were graft and patient survival. A total of 117, 3437, and 4379 recipients underwent DCD-FHF, DBD-FHF and DCD-non-FHF, respectively. One-year graft survival in DCD-FHF was inferior to DBD-FHF (72.9% vs. 83.8%, p = .002), but comparable to DCD-non-FHF (72.9% vs. 82.7%, p = .23). However, 3- and 5-year graft survival in DCD-FHF were comparable to DBD-FHF (67.9 vs. 77.6%, p = .63; 57.8% vs. 73.2%, p = .27) and DCD-non-FHF (67.9% vs. 72.9%, p = .44; 57.8% vs. 66.6%, p = .06). One-, 3-, and 5-year patient survival were also comparable among the three groups. Graft and patient survival in DCD-FHF improved over the study period. Multivariable analysis identified recipient age, male gender, African American ethnicity, donor age, and cold ischemia time as predictors of graft and patient survival in FHF, while DCD status was only predictive of graft survival. Long-term graft survival and patient survival in DCD-FHF are comparable to DBD-FHF and DCD-non-FHF. Consideration of DCD in FHF could help expand the donor pool in this subset of critically ill patients.

Excessive arachidonic acid induced actin bunching remodeling and podocyte injury via a PKA-c-Abl dependent pathway.

Recent studies have shown that serum secretory phospholipase A2 group IB (sPLA2-IB) is associated with proteinuric kidney diseases and plays a pivotal role in podocyte injury via its natural receptor. Arachidonic acid (AA), as a major metabolite of sPLA2-IB, regulates the actin bungling remodeling and contributes to the podocyte injury. However, the underlying mechanism of AA in the regulation of podocyte actin remodeling and human podocyte injury is unclear. Here, we reported that AA induced F-actin cytoskeletal ring formation and promoted protein kinase A (PKA), nephrin and c-Abl phosphorylation. Moreover, AA promoted c-Abl translocation from the nucleus to the cytoplasm and increased the recruitment of c-Abl to p-nephrin by the interaction between them. H89 (PKA inhibitor) provided protection against AA-induced F-actin bunching remodeling, down-regulated nephrin phosphorylation, and suppressed the c-Abl translocation and activation. STI571 (c-Abl inhibitor) also improved the AA associated F-actin bunching remodeling. In addition, H89 and STI571 both alleviated apoptosis and adhesion damage of podocyte. These results indicate that an excess of AA treatment is detrimental to the podocyte actin cytoskeleton and promotes podocyte injury due to the activation of PKA-c-Abl signaling.

Effects of Probiotics on Malnutrition and Health-Related Quality of Life in Patients Undergoing Peritoneal Dialysis: A Randomized Controlled Trial.

OBJECTIVE: Alterations in the gut microbiota and host responses have been implicated in the progression of end-stage renal disease, increased cardiovascular risk, uremic toxicity, and inflammation. The purpose of this study was to evaluate the clinical efficacy of probiotics on malnutrition and health-related quality of life in patients undergoing peritoneal dialysis (PD). DESIGN AND METHODS: A total of 116 patients undergoing PD were randomly divided into an intervention group (n = 58) and a control group (n = 58). The intervention group received a daily dose of probiotics (1 × 109 CFU/day, i.e., 2 capsules, tid) for 2 months, while the control group did not receive probiotics during the same period. Biochemical indicators, physical measurements, and scores on the SF-36 were measured before and 2 months after the intervention. RESULTS: A total of 98 patients completed the study (50 in the intervention group and 48 in the control group). Among patients receiving probiotics, the levels of high-sensitivity C-reactive protein and interleukin-6 decreased after 2 months of treatment, while the serum albumin levels, upper arm circumference, and triceps skinfold thickness increased significantly. The probiotic group had higher scores on the physical functioning and social functioning domains than the control group after 2 months. CONCLUSIONS: Probiotics could significantly decrease the serum levels of high-sensitivity C-reactive protein and interleukin-6 and increase the serum albumin levels, upper arm circumference, and triceps skinfold thickness in patients undergoing PD. As a result, malnutrition and health-related quality of life partially improved after probiotic supplementation in patients undergoing PD.

The Association Between Lung Recipient Travel Distance and Posttransplant Survival.

INTRODUCTION: Recipient travel distance may be an unrecognized burden in lung transplantation. DESIGN: Retrospective single-center cohort study of all adult (≥18 years) first-time lung-only transplants from January 1, 2010, until February 28, 2017. Recipient distance to transplant center was calculated using the linear distance from the recipient's home zip code to the Cleveland Clinic in Cleveland, Ohio. RESULTS: 569 recipients met inclusion criteria. Posttransplant graft survival was 85%, 88%, 91%, and 91% at 1 year and 49%, 52%, 57%, and 56% at 5 years posttransplant for recipient travel distances of ≤50, >50 to ≤250, >250 to ≤500, and >500 miles, respectively ( P = .10). DISCUSSION: We found no significant relationship between recipient travel distance and posttransplant graft survival. In carefully selected recipients, travel distance is not a significant barrier to successful posttransplant outcomes which may be important for patient decision-making and donor allocation policy. These data should be validated in a national cohort.

Trends in Renal Transplantation Rates in Patients with Congenital Urinary Tract Disorders.

PURPOSE: Improved bladder and renal management benefit patients with congenital uropathy and congenital pediatric kidney disease. This may translate to delayed initial renal transplantation in these patients, and improved graft and patient survival. Our primary study purpose was to determine whether patients with congenital uropathy and congenital pediatric kidney disease have demonstrated later time to first transplantation and/or graft survival. MATERIALS AND METHODS: SRTR (Scientific Registry of Transplant Recipients) was analyzed for first renal transplant and survival data in patients with congenital uropathy and congenital pediatric kidney disease from 1996 to 2012. Congenital uropathy included chronic pyelonephritis/reflux, prune belly syndrome and congenital obstructive uropathy. Congenital pediatric kidney disease included polycystic kidney disease, hypoplasia, dysplasia, dysgenesis, agenesis and familial nephropathy. RESULTS: A total of 7,088 patients with congenital uropathy and 24,315 with congenital pediatric kidney disease received a first renal transplant from 1996 to 2012. A significant shift was seen in both groups toward older age at initial renal transplantation in those 18 through 64 years old. In the congenital uropathy group this effect was most facilitated by decreased renal transplantion in patients between 18 and 35 years old (38% in 1996 vs 26% in 2012). The congenital pediatric kidney disease group showed a substantial decrease in patients who were 35 to 49 years old (from 39% to 29%). At 10-year followup the congenital uropathy group showed better graft and patient survival than the congenital pediatric kidney disease group. However, aged matched comparison revealed comparable survival rates in the 2 groups. CONCLUSIONS: Analysis of trends in the last 14 years demonstrated that patients with both lower and upper tract congenital anomalies experienced delayed time to the first renal transplant. Furthermore, patients had similar age matched graft and patient survival whether the primary source of renal demise was the congenital lower or upper tract. These findings may indicate that improved urological and nephrological care are promoting renal preservation in both groups.

sPLA2-IB Level Correlates with Hyperlipidemia and the Prognosis of Idiopathic Membranous Nephropathy.

Recent studies suggested that serum secretory phospholipase A2 group IB (sPLA2-IB) was increased in idiopathic membranous nephropathy (IMN). However, the interference of high lipemia on the sPLA2-IB levels was not taken into account in these studies. The present study aimed to investigate the correlation between sPLA2-IB and lipemia, and the clinical merit of sPLA2-IB in the prediction of prognosis of IMN patients. A total of 64 IMN patients, 39 immunoglobulin A nephropathy (IgAN) patients and 64 healthy controls were included in the study. The levels of serum sPLA2-IB, lipemia and proteinuria were measured. Fifty IMN patients were followed up for 6 months. Pathologic stages were made for all IgAN and IMN patients. The results showed that the levels of serum sPLA2-IB, cholesterol and low-density lipoprotein cholesterol (LDL-C) were significantly higher, and the levels of albumin and high-density lipoprotein cholesterol (HDL-C) were significantly lower in IMN patients than in healthy controls and IgAN patients. Serum sPLA2-IB levels were also found to be higher in IgAN patients than in heathy controls, but the association of serum sPLA2-IB levels with proteinuria, cholesterol and albumin was only shown in IMN patients. Antibody against M-type receptor for secretory phospholipase A2 (PLA2R1) was positive in 81.3% IMN patients. Glomerular sPLA2-IB deposition, podocyte fused processes, and density deposition on thickened basement membrane were seen in IMN patients, but not in IgAN patients. IMN patients with lower sPLA2-IB and proteinuria levels were found to have better outcome after the 6-month follow-up. In IMN patients, sPLA2-IB levels were significantly increased in both serum and renal tissue. In conclusion, serum sPLA2-IB was closely correlated with proteinuria, albumin and cholesterol, and IMN patients with lower sPLA2-IB levels were more likely to achieve a better outcome.

A Contemporary Analysis of Outcomes and Modifiable Risk Factors of Ethnic Disparities in Kidney Transplantation.

OBJECTIVE: The aim of this study was to provide a contemporary analysis of longitudinal kidney transplant outcomes and to evaluate potential causes of ethnic disparities among African American (AA) and Caucasian American (CA) patients undergoing kidney transplantation at our institution. PATIENTS AND METHODS: 1400 patients were identified who underwent kidney transplantation from 2003 to 2013 from a large, academic institution in Cleveland, OH. Relevant recipient and donor demographic and clinical covariates were obtained from an institutional transplant database. Simple descriptive statistics and comparative survival analyses were performed to assess overall survival and graft survival. RESULTS: The final cohort was comprised of 341 AA and 1059 CA patients. AAs were less likely to receive a living donor transplant (27.6% vs. 57.2%, p < 0.001) compared to CAs. Overall patient survival did not significantly differ between the two groups even when stratified by ethnicity. However, AAs had a significantly lower rate of graft survival (p < 0.001). On stratified analysis, there was no difference in the rate of graft survival among AAs and CAs who received living donor grafts. On univariate analysis, AAs demonstrated higher rates of immunosuppression non-compliance and chronic rejection (both p < 0.05). On multivariate analysis, AA recipient ethnicity (HR 1.56, p = 0.047), recipient history of diabetes (HR 1.67, p < 0.001), and AA donor ethnicity (HR 1.56, p = 0.047) were significantly associated with graft failure. CONCLUSION: AAs undergoing deceased donor renal transplantation demonstrated lower graft survival compared to CAs. Conversely, this disparity did not exist among AAs undergoing living donor transplantation. AAs had higher rates of deceased donor transplantation, immunosuppression non-compliance, chronic rejection, and diabetes. Opportunities exist to use patient education, alternative immunosuppression regimens, and living transplantation to close the ethnic disparity in renal allograft survival.

Determinants of arterial wall remodeling during lipid-lowering therapy: serial intravascular ultrasound observations from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial.

BACKGROUND: Coronary plaque progression and instability are associated with expansive remodeling of the arterial wall. However, the remodeling response during plaque-stabilizing therapy and its relationship to markers of lipid metabolism and inflammation are incompletely understood. METHODS AND RESULTS: Serial intravascular ultrasound (IVUS) data from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial were obtained during 18 months of intensive versus moderate lipid-lowering therapy. In a subgroup of 210 patients, focal coronary lesions with mild luminal narrowing were identified. Lumen area, external elastic membrane (EEM) area, and plaque area were determined at the lesion and proximal reference sites at baseline and during follow-up. The remodeling ratio (RR) was calculated by dividing the lesion EEM area by the reference EEM area. The relationship between the change in remodeling, change in plaque area, lipid profile, and inflammatory markers was examined. At the lesion site, a progression in plaque area (8.9+/-25.7%) and a decrease in the RR (-3.0+/-11.2%) occurred during follow-up. In multivariable analyses, the percentage change in plaque area (P<0.0001), baseline RR (P<0.0001), baseline lesion lumen area (0.019), logarithmic value of the change in high-sensitivity C-reactive protein (P=0.027), and hypertension at baseline (P=0.014) showed a significant, direct relation with the RR at follow-up. Lesion location in the right coronary artery (P=0.006), percentage change in triglyceride levels (P=0.049), and age (P=0.037) demonstrated a significant, inverse relation with the RR at follow-up. Changes in LDL cholesterol, HDL cholesterol, and treatment group demonstrated no significant associations. CONCLUSIONS: Constrictive remodeling of the arterial wall was observed during plaque-stabilizing therapy with statin medications and appears related to their antiinflammatory effects.

Usefulness of postexercise ankle-brachial index to predict all-cause mortality.

Peripheral arterial disease predicts future cardiovascular events and all-cause mortality. Conventional methods of assessment might underestimate its true prevalence. We sought to determine whether a postexercise ankle-brachial index (ABI), not only improved peripheral arterial disease detection, but also independently predicted death. This was an observational study of consecutive patients referred for ABI measurement before and after the fixed-grade treadmill or symptom-limited exercise component to a noninvasive vascular laboratory from January 1990 to December 2000. The subjects were classified into 2 groups. Group 1 included patients with an ABI of ≥0.85 before and after exercise, and group 2 included patients with a normal ABI at rest but <0.85 after exercise. A total of 6,292 patients underwent ABI measurements with exercise during the study period. Propensity score matching of the groups was performed to minimize observational bias. Overall mortality, as determined using the United States Social Security death index, was the end point. The 10-year mortality rate of groups 1 and 2 was 32.7% and 41.2%, respectively. An abnormal postexercise ABI result independently predicted mortality (hazard ratio 1.3, 95% confidence interval 1.07 to 1.58, p = 0.008). Additional independent predictors of mortality were age, male gender, diabetes, and hypertension. After the exclusion of patients with a history of cardiovascular events, the predictive value of an abnormal postexercise ABI remained statistically significant (hazard ratio 1.67, 95% confidence interval 1.29 to 2.17, p <0.0001). In conclusion, our results have shown that the postexercise ABI is a powerful independent predictor of all-cause mortality and provides additional risk stratification beyond the ABI at rest.

Signs and symptoms of heart failure: are you asking the right questions?

BACKGROUND: Patients may not verbalize common and atypical signs and symptoms of heart failure and may not understand their association with worsening disease and treatments. OBJECTIVES: To examine prevalence of signs and symptoms relative to demographics, care setting, and functional class. METHODS: A convenience sample of 276 patients (164 ambulatory, 112 hospitalized) with systolic heart failure completed a 1-page checklist of signs and symptoms experienced in the preceding 7 days (ambulatory) or in the 7 days before hospitalization. Demographic and medical history data were collected. RESULTS: Mean age was 61.6 (SD, 14.8) years, 65% were male, 58% were white, and 45% had ischemic cardiomyopathy. Hospitalized patients reported more sudden weight gain, weight loss, severe cough, low/orthostatic blood pressure, profound fatigue, decreased exercise, restlessness/confusion, irregular pulse, and palpitations (all P < .05). Patients in functional class IV reported more atypical signs and symptoms of heart failure (severe cough, nausea/vomiting, diarrhea or loss of appetite, and restlessness, confusion, or fainting, all P