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Hypertension is associated with vascular injury, which contributes to end-organ damage. MicroRNAs regulating mRNAs have been shown to play a role in vascular injury in hypertensive mice. We aimed to identify differentially expressed microRNAs and their mRNA targets in small arteries of hypertensive patients with/without chronic kidney disease (CKD) to shed light on the pathophysiological molecular mechanisms of vascular remodeling.Normotensive individuals and hypertensive patients with/without CKD were recruited ( n = 15-16 per group). Differentially expressed microRNAs and mRNAs were identified uniquely associated with hypertension (microRNAs: 10, mRNAs: 68) or CKD (microRNAs: 68, mRNAs: 395), and in both groups (microRNAs: 2, mRNAs: 32) with a P less than 0.05 and a fold change less than or greater than 1.3 in subcutaneous small arteries ( n = 14-15). One of the top three differentially expressed microRNAs, miR-338-3p that was down-regulated in CKD, presented the best correlation between RNA sequencing and reverse transcription-quantitative PCR (RT-qPCR, R2 = 0.328, P 0.001). Profiling of human aortic vascular cells showed that miR-338-3p was mostly expressed in endothelial cells. Two of the selected top nine up-regulated miR-338-3p predicted targets, glutathione peroxidase 3 ( GPX3 ) and protein tyrosine phosphatase receptor type S ( PTPRS ), were validated with mimics by RT-qPCR in human aortic endothelial cells ( P 0.05) and by a luciferase assay in HEK293T cells ( P 0.05).A distinct transcriptomic profile was observed in gluteal subcutaneous small arteries of hypertensive patients with CKD. Down-regulated miR-338-3p could contribute to GPX3 and PTPRS up-regulation via the canonical microRNA targeting machinery in hypertensive patients with CKD.http://links.lww.com/HJH/C27.

Context: Patients treated with maintenance hemodialysis experience significant symptom burden resulting in impaired quality of life. However, the association of patient reported symptom burden and the risk of healthcare use for patients with end stage kidney disease on hemodialysis has not been fully explored. Objectives: To investigate if higher symptom burden, assessed by the Edmonton Symptom Assessment System-revised (ESASr), is associated with increased healthcare use in patients with end stage kidney disease on hemodialysis. Methods: Prospective, single-center, study of adult patients on HD. Participants completed the ESASr questionnaire at enrollment. Baseline demographic, clinical information as well as healthcare use events during the 12-month following enrollment were extracted from medical records. The association between symptom burden and healthcare use was examined with a multivariable adjusted negative binomial model. Results: Mean (SD) age of the 80 participants was 71 (13) years, 56% diabetic, and 70% male. The median (IQR) dialysis vintage was 2 (1–4) years. In multivariable adjusted models, higher global [incident rate ratio (IRR) 1.02, 95% confidence interval (CI) 1.00–1.04, p = .025] and physical symptom burden score [IRR 1.03, CI 1.00–1.05, p = .034], but not emotional symptom burden score [IRR 1.05, CI 1.00–1.10, p = .052] predicted higher subsequent healthcare use. Conclusions: Our preliminary evidence suggests that higher symptom burden, assessed by ESASr may predict higher risk of healthcare use amongst patients with end stage kidney disease on hemodialysis. Future studies need to confirm the findings of this preliminary study and to assess the utility of ESASr for systematic symptom screening.

(1) Objective: to determine if a brief mindfulness intervention (BMI) and a health education program (HEP) could improve measures of insomnia in patients undergoing hemodialysis. (2) Methods: this was a planned secondary analysis of a randomized controlled trial of BMI vs. HEP for hemodialysis patients with depression and/or anxiety symptoms. The primary outcome for the analysis was the Athens Insomnia Scale (AIS). The secondary outcome was consolidation of daily inactivity (ConDI), an actigraphy measure that describes sleep continuity and is based on a sleep detection algorithm validated by polysomnography. We also explored whether changes in AIS and ConDI were associated with changes in depression, anxiety, and quality of life scores over 8-week follow-up. (3) Results: BMI and HEP groups did not differ significantly from one another. Exposure to BMI or HEP improved sleep quality (baseline AIS 9.9 (±5.0) vs. 8-week follow-up 6.4 (±3.9), (V = 155.5, p = 0.015)), but not ConDI. Improvements in AIS were associated with lower depression scores (Rho = 0.57, p = 0.01) and higher quality-of-life scores (Rho = 0.46, p = 0.04). (4) Conclusions: mindfulness and HEP may be helpful interventions to improve self-reported sleep quality in patients undergoing hemodialysis. Decreases in insomnia scores were associated with decreased depression symptoms and increased quality of life scores.

Background: Hypertension (HTN) causes vascular injury identified by endothelial dysfunction, vascular stiffening, and remodeling, which contributes to kidney damage leading to chronic kidney disease (CKD). MicroRNAs (miRNAs) repress/degrade target mRNAs. Their role in vascular injury in HTN remains unclear. We aimed to identify differentially expressed (DE) miRNAs in gluteal subcutaneous arteries of patients with HTN associated or not with CKD to shed light on the pathophysiological molecular mechanisms. Methods: Normotensive subjects and patients with HTN associated or not with CKD grades 3-4 were studied (n=15-16). Small arteries were isolated from gluteal subcutaneous biopsies, RNA extracted and small and total RNA sequencing performed by Illumina HiSeq-2500. DE genes were identified with a P 1.3. Top 3 DE miRNAs ( P 2, mean read count number (MRCN) >3,000 in all groups and having predicted mRNA targets) were selected for validation by reverse transcription-quantitative PCR (RT-qPCR). The mRNA targets of the top selected miRNA were predicted by TargetScan with P 1.5 and MRCN>150 and the top 9 targets were validated by RT-qPCR using gain- and loss-of-function in human aortic endothelial cells (HAECs). Gene ontology enrichment analysis (GOEA) was done in Cytoscape. Results: DE miRNAs and mRNAs were identified uniquely associated with HTN (miRNAs: 10, mRNAs: 68), CKD (miRNAs: 68, mRNAs: 395), and in both groups (miRNAs: 2, mRNAs: 32). miR-338-3p presented the best correlation between RNA sequencing and RT-qPCR (R 2 =0.328, P PTPRS , FC: 0.80±0.08 vs 1.00±0.00) and glutathione peroxidase 3 ( GPX3 , FC: 0.88±0.04 vs 1.00±0.00) were down-regulated in HAECs transfected with miR-338-3p mimics ( P GPX3 with oxidative stress detoxification ( q PTPRS with the immune system, neuronal system and developmental process ( q Conclusion: Down-regulated miR-338-3p in gluteal subcutaneous small arteries of hypertensive patients with CKD targets PTPRS and GPX3 that may play a role in vascular injury in HTN.

Background: Hypertension (HTN) is associated with subclinical target organ damage including cardiac, vascular and kidney injury. The immune system plays a role in hypertension and target organ damage. Activation of T cells has been reported among peripheral blood mononuclear cells (PBMCs) of patients with HTN. MicroRNAs (miRNAs) are crucial post-transcriptional regulators of immune cells. Whether miRNAs play a role in the activation of immune cells in hypertension complicated by target organ damage in humans remains unknown. We aimed to address this question by identifying differentially expressed (DE) miRNAs and their mRNA targets in PBMCs of patients with hypertension complicated or not with metabolic syndrome (MetS) or chronic kidney disease (CKD). Methods: Normotensive subjects and patients with hypertension (HTN) associated or not with at least 2 other features of MetS or CKD were studied (n=15-16). PBMCs were isolated from blood, RNA extracted for small and total RNA sequencing (RNA-seq) using Illumina HiSeq-2500 and data were analyzed using a systems biology approach. MiRDeep2 was used for novel miRNAs prediction, miRNA annotation and counting. TargetScan 7.07 was used to predict DE miRNA targets with weighted context score percentile >50%. DE genes miRNAs and mRNAs were identified with fold change (FC) >1.5 and P 2 and mean read count number (MRCM) >500, and with predicted targets with MRCM>300 were validated by reverse transcription-quantitative PCR (RT-qPCR). Results: DE miRNAs, mRNAs and non-coding RNAs were identified in HTN (22, 19 and 0), MetS (57, 401 and 11) and CKD (6, 26 and 2) compared to NTN. TargetScan predicted that 7 miRNAs target 3 mRNAs in NTN, 57 miRNAs target 55 mRNAs in MetS and 3 miRNAs target 2 mRNAs in CKD. DE miR-409-5p (FC: 0.54±0.10 vs 1.00±0.09, P P P 2 =0.40, P 2 =0.55, P 2 =0.37, P Conclusion: This study showed that DE miR-409-5p, miR-411-5p and miR-pl-86 may play a role in HTN associated with MetS.

Background: Between 20–50% of patients undergoing maintenance dialysis for end-stage kidney disease experience symptoms of depression and/or anxiety, associated with increased mortality, greater health care utilization, and decreased quality of life. It is unknown whether mindfulness-based interventions can improve depression and anxiety symptoms in patients receiving this treatment. Methods: We conducted an 8-week multicenter randomized controlled trial comparing a brief mindfulness intervention (BMI) vs. an active control (Health Enhancement Program [HEP]) in 55 patients receiving dialysis with symptoms of depression and/or anxiety. The primary outcome was change in Patient Health Questionnaire-9 (PHQ-9) depression scores, with a primary analysis in participants with baseline PHQ-9 ≥ 10, and a secondary analysis including all participants. The secondary outcome was change in Generalized Anxiety Disorder-7 (GAD-7) anxiety scores with corresponding primary and secondary analyses. Results: Both BMI and HEP reduced depressive symptoms, with no difference between trial arms (PHQ-9 change = −7.0 vs. −6.1, p = 0.62). BMI was more effective than HEP in reducing anxiety (GAD-7 change = −8.7 vs. −1.4, p = 0.01). Secondary analyses revealed no differences between arms. Conclusions: For patients undergoing dialysis, both BMI and HEP may be helpful interventions for depression symptoms, and BMI may be superior to HEP for anxiety symptoms. Mindfulness-based and other psychosocial interventions may be further evaluated in those undergoing dialysis as treatment options for symptoms of depression and anxiety.

Background. Sodium glucose cotransport (SGLT)-2 inhibitors are the newest class of antihyperglycemic agents used as second- or third-line treatment in the management of type 2 diabetes. Although the use of SGLT-2 inhibitors has not been shown to cause nephrotoxicity, there have been case reports of SGLT-2 inhibitor use being associated with acute kidney injury. Case Presentation. A 72-year-old woman with a history of type 2 diabetes and no known chronic renal insufficiency presented to the emergency room with a 3-day history of nausea, vomiting, and increased somnolence. She was found to have potassium level of 7.4 (normal: 3.5-5.5) mmol/L and a markedly elevated creatinine level at 1154 (normal: 45-95) μmol/L. Imaging of the abdomen and pelvis did not reveal any findings of obstruction. Urine microscopy showed many granular casts. In the absence of other causes for her clinical presentation, the patient was diagnosed with acute kidney injury secondary to ischemic acute tubular necrosis, with canagliflozin use likely an important contributing factor. Conclusions. Physicians should inform patients to stop the use of SGLT-2 inhibitors when patients are unable to maintain hydration or during acute illness. Use of SGLT-2 inhibitors in managing type 2 diabetes should be done with caution among more vulnerable populations, including individuals with cognitive impairment and the elderly.

BACKGROUND Hypertension (HTN) is associated with target organ damage such as cardiac, vascular, and kidney injury. Several studies have investigated circulating microRNAs (miRNAs) as biomarkers of cardiovascular disease, but few have examined them as biomarker of target organ damage in HTN. We aimed to identify circulating miRNAs that could serve as biomarkers of HTN-induced target organ damage using an unbiased approach. METHODS AND RESULTS Fifteen normotensive subjects, 16 patients with HTN, 15 with HTN associated with other features of the metabolic syndrome (MetS), and 16 with HTN or chronic kidney disease (CKD) were studied. Circulating RNA extracted from platelet-poor plasma was used for small RNA sequencing. Differentially expressed (DE) genes were identified with a threshold of false discovery rate CONCLUSIONS We identified decreased circulating let-7g-5p and miR-191-5p as independent biomarkers of CKD among patients with HTN, which could have pathophysiological and therapeutic implications.

Background: Hypertension (HTN) and chronic kidney disease (CKD) are associated with vascular damage characterized by vascular remodeling and stiffening and endothelial dysfunction. miRNAs are small non-coding RNA that regulate gene expression by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation or translational repression. Their implication in vascular injury remains unclear. We aimed to identify differentially expressed (DE) miRs in small arteries of HTN and CKD human subjects to gain insight into pathophysiological molecular mechanisms in these conditions. Methods: Normotensive, HTN [systolic blood pressure (BP) >135 mmHg or diastolic BP of 85-115 mmHg with BpTRU] and CKD subjects (estimated glomerular filtration rate 2 ) (n=15-16) were studied. Small arteries were isolated from subcutaneous gluteal biopsies and RNA extracted for small and total RNA sequencing using Illumina HiSeq-2500 and further studied using a systems biology approach. Differentially expressed (DE) genes were identified with fold change >1.5 and fold discovery rate Results: DE miRs were identified ( P r =0.91, P -16 ), uniquely associated with CKD, was studied further. miR-338-3p and some of its predicted targets were highly expressed in human aortic endothelial cells (HAECs). Two of them, alkaline ceramidase 2 ( ACER2 ) and glutathione peroxidase 3 (GPX3), were up-regulated by ~36% and ~60% in HAECs transfected with anti-miR-338-3p, respectively ( P ACER2 or GPX3 3’ untranslated transcribed region miR-338-3p-5p binding sites ( P Conclusion: miR-338-3p was down-regulated in small arteries, which was uniquely associated with CKD. ACER2 and GPX3 , identified as miR-338-3p targets, may play a role in vascular injury in CKD.

Background End-stage renal disease is associated with significant morbidity, high-symptom burden, and health care use. Studies have not yet assessed psychosocial distress and health care utilization in this population. Objective This study examines psychosocial distress and its association with hospitalization and emergency room (ER) visits in patients on maintenance hemodialysis (HD). Methods The Distress Assessment and Response Tool (DART) was administered to 80 adults on HD in a single treatment center. The DART assessed for anxiety, depression, and social distress. Health care utilization data were extracted prospectively from electronic medical charts. The time between psychosocial distress and hospitalization or ER visits during 12-month follow-up was examined using Cox proportional hazard models. Results Overall 46% of the sample reported psychosocial distress, with 33% screening above the threshold for depression, 14% for anxiety, and 36% for significant social distress. In multivariable regression adjusting for age, sex, and comorbidity, the presence of psychosocial distress was associated with shorter time to hospitalization (hazard ratio: 2.4 [1.1, 5.0], p = 0.03) during 12-month follow-up. Psychosocial distress was not significantly associated with ER visits in either univariable (hazard ratio: 1.3 [0.7, 2.3], p = 0.5) or multivariable (hazard ratio: 1.4 [0.8, 2.6], p = 0.3) analyses. Conclusion Psychosocial distress is frequent in patients undergoing maintenance HD and is associated with shorter time to hospitalization. Future longitudinal studies should examine if health service use can be reduced through routine distress screening and psychosocial distress intervention.

Vascular calcification increases the risk of cardiovascular disease and death in patients with chronic kidney disease (CKD). Increased activity of mammalian target of rapamycin complex 1 (mTORC1) and endoplasmic reticulum (ER) stress-unfolded protein response (UPR) are independently reported to partake in the pathogenesis of vascular calcification in CKD. However, the association between mTORC1 activity and ER stress-UPR remains unknown. We report here that components of the uremic state [activation of the receptor for advanced glycation end products (RAGE) and hyperphosphatemia] potentiate vascular smooth muscle cell (VSMC) calcification by inducing persistent and exaggerated activity of mTORC1. This gives rise to prolonged and excessive ER stress-UPR as well as attenuated levels of sestrin 1 ( Sesn1) and Sesn3 feeding back to inhibit mTORC1 activity. Activating transcription factor 4 arising from the UPR mediates cell death via expression of CCAAT/enhancer-binding protein (c/EBP) homologous protein (CHOP), impairs the generation of pyrophosphate, a potent inhibitor of mineralization, and potentiates VSMC transdifferentiation to the osteochondrocytic phenotype. Short-term treatment of CKD mice with rapamycin, an inhibitor of mTORC1, or tauroursodeoxycholic acid, a bile acid that restores ER homeostasis, normalized mTORC1 activity, molecular markers of UPR, and calcium content of aortas. Collectively, these data highlight that increased and/or protracted mTORC1 activity arising from the uremic state leads to dysregulated ER stress-UPR and VSMC calcification. Manipulation of the mTORC1-ER stress-UPR pathway opens up new therapeutic strategies for the prevention and treatment of vascular calcification in CKD.

Background There is conflicting evidence of benefit versus harm for warfarin anticoagulation in hemodialysis patients with atrial fibrillation. This equipoise may be explained by suboptimal Time in Therapeutic Range (TTR), which correlates well with thromboembolic and bleeding complications. This study aimed to compare nephrologist-led management of warfarin therapy versus that led by specialized anticoagulation clinic. Methods In a retrospective cohort of chronic hemodialysis patients from two institutions (Institution A: Nephrologist-led warfarin management, Institution B: Anticoagulation clinic-led warfarin management), we identified patients with atrial fibrillation who were receiving warfarin for thromboembolic prophylaxis. Mean TTRs, proportion of patients achieving TTR ≥ 60%, and frequency of INR testing were compared using a logistic regression model. Results In Institution A, 16.7% of hemodialysis patients had atrial fibrillation, of whom 36.8% were on warfarin. In Institution B, 18% of hemodialysis patients had atrial fibrillation, and 55.5% were on warfarin. The mean TTR was 61.8% (SD 14.5) in Institution A, and 60.5% (SD 15.8) in Institution B (p-value 0.95). However, the proportion of patients achieving TTR ≥ 60% was 65% versus 43.3% (Adjusted OR 2.22, CI 0.65–7.63) and mean frequency of INR testing was every 6 days versus every 13.9 days in Institutions A and B respectively. Conclusions There was no statistical difference in mean TTR between nephrologist-led management of warfarin and that of clinic-led management. However, the former achieved a trend toward a higher proportion of patients with optimal TTR. This improved therapeutic results was associated with more frequent INR monitoring.

Background: Chronic kidney disease (CKD) is a global health burden with a worldwide prevalence of 13.4% for stage 5 and 10.6% for stage 3-5. There is an epidemiological association between hypertension (HTN) and CKD. The prevalence of high blood pressure (BP) has been reported to be over 85% in stage 3 and over 90% in stage 4-5 CKD patients. Circulating cell-free small non-coding RNAs called microRNA (miRNA) have been shown to associate with different pathologies including cancer and cardiovascular disease, and accordingly possesses potential to serve as biomarkers with clinical application. We aimed to identify differentially expressed (DE) miRNAs that may be related to CKD. Methods and Results: Normotensive, HTN (systolic BP > 135 mmHg or diastolic BP of 85-115 mmHg with BPtru) and CKD (estimated glomerular filtration rate (eGFR) < 60mL/min/m 2 ) subjects (n=15-16 per group) were studied. Platelet-free plasma was isolated by a 2-step centrifugation (1000xg followed by 10,000xg) from 6 ml total blood. Plasma miRNAs were extracted using the QIAamp Circulating Nucleic Acid Kit. The quantity and quality of RNA were assessed using an Agilent 2100 Bioanalyzer. cDNA libraries were prepared using the TruSeq Small RNA Library Prep Kit, and sequenced with the HiSeq 2500 platform. FastQC was used for quality control. Sequences were mapped by STAR to the hg38 genome and annotated by miRDeep2. DE miRNAs were identified using EdgeR, which found 6 up-regulated and 3 down-regulated miRNAs uniquely associated with the HTN group, 2 up-regulated and 12 down-regulated miRNAs uniquely associated with the CKD group and 3 down-regulated miRNAs in both groups ( P P P P Conclusions and Perspectives: DE platelet-free plasma miRNAs were identified in HTN and CKD patients. Some miRNAs may have the potential to serve as biomarkers in CKD.

Cardiovascular disease is the principal cause of morbidity and mortality in patients with diabetes mellitus. The incidence or progression of kidney disease is also common in these patients. Several clinical trials have established the efficacy of angiotensin receptor blockers for the prevention of adverse cardiovascular and renal outcomes in this population and are summarized in this review article. Head-to-head comparison of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors has shown similar cardioprotective and renoprotective properties of both medication classes. However, angiotensin receptor blockers have an improved safety profile with fewer episodes of cough and angioedema and may be the agent of choice in patients with diabetes and hypertension. Novel therapeutic strategies, such as those that include a mineralocorticoid receptor blocker or a selective sodium-glucose cotransporter type 2 inhibitor, may further protect patients with diabetes from cardiovascular and renal complications.

It is unclear whether warfarin is protective or harmful in patients with ESRD and atrial fibrillation. This state of equipoise raises the question of whether alternative anticoagulants may have a therapeutic role. We aimed to determine apixaban pharmacokinetics at steady state in patients on hemodialysis. Seven patients received apixaban 2.5 mg twice daily for 8 days. Blood samples were collected before and after apixaban administration on days 1 and 8 (nondialysis days). Significant accumulation of the drug was observed between days 1 and 8 with the 2.5-mg dose. The area under the concentration-time curve from 0 to 24 hours increased from 628 to 2054 ng h/ml (P

There appears to be a broad consensus among professional health organizations that a blood pressure (BP) of 130/80 mm Hg or less is the recommended therapeutic BP target for subjects with diabetes mellitus. This review focuses on key studies that have examined the relationship between BP reduction and its impact on diabetic complications. An attempt is being made to identify the BP level at which maximum protection against diabetic complications is conferred, and below which further reduction no longer delivers a benefit that exceeds risk. Specific attention has been accorded to data contributing to establishing ideal BP goals in diabetic patients with nephropathy. On the basis of recent studies, it would appear that a BP below 140/90 mm Hg should be recommended for all diabetic individuals, and around 135/85 mm Hg for most. BP should be closer to, but not below, 130/80 mm Hg for those subjects at the highest cardiovascular risk. For those diabetic subjects at highest risk for stroke, lower BP may provide greater protection against stroke as shown in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. In younger individuals with diabetes and hypertension of shorter duration, it may be possible to lower BP below 130/80 mm Hg without untoward side effects and in fact with cardiovascular benefit, but this remains to be demonstrated. The ideal BP goal in diabetic patients with nephropathy remains questionable, and for now, the recommended target must be considered the same as that for the general diabetic population.

A 71-year-old man presented to the emergency department with a 2-week history of worsening cough and shortness of breath. The patient had a history of end-stage renal disease secondary to diabetic nephropathy, and he had received a deceased donor renal transplant 3 years before presentation. His baseline estimated glomerular filtration rate was approximately 50 ml/min. He was also known to have hypertension, type 2 diabetes mellitus, hyperlipidemia, coronary artery disease, and active hepatitis B. His medications included extended-release tacrolimus 16 mg daily, mycophenolic acid 720 mg twice daily, prednisone 5 mg daily, lamivudine, valsartan, metoprolol, doxazocin, atorvastatin, pantoprazole, and insulin. On examination, the patient was hemodynamically stable but tachypneic, with an oxygen saturation of 87% while breathing ambient air. His jugular venous pressure was not elevated, and there was no peripheral edema. His cardiac and respiratory examination was otherwise unremarkable. On laboratory investigations, the patient was noted to have hypercalcemia (total corrected calcium 3.09 mmol/l) which was not present during routine lab testing 2 weeks earlier. His parathyroid hormone level was suppressed. Renal function was unchanged from his previous values. Pertinent laboratory data are presented in Table 1. Chest radiograph on presentation showed diffuse increased markings over the left lung field with relative oligemia of the right lung. Further investigations included a negative ventilation perfusion scan and a normal transthoracic echocardiogram. Computed tomography (CT) of the chest revealed diffuse ground-glass opacities, involving the posterior portions of both lungs and the apices bilaterally. In the context of the hypercalcemia, CT scan of the abdomen and pelvis was performed, and there was no evidence of an underlying malignancy.

Delayed graft function (DGF) and slow graft function (SGF) are ischemia-reperfusion-associated acute kidney injuries (AKI) that decrease long-term graft survival after kidney transplantation. Regulatory T (Treg) cells are protective in murine AKI, and their suppressive function predictive of AKI in kidney transplantation. The conventional Treg cell function coculture assay is however time-consuming and labor intensive. We sought a simpler alternative to measure Treg cell function and predict AKI.In this prospective observational cohort study, pretransplant recipient circulating CD4+CD25+CD127lo/- and CD4+CD127lo/- tumor necrosis factor receptor 2 (TNFR2)+ Treg cells were measured by flow cytometry in 76 deceased donor kidney transplant recipients (DGF, n = 18; SGF, n = 34; immediate graft function [IGF], n = 24). In a subset of 37 recipients, pretransplant circulating Treg cell-suppressive function was also quantified by measuring the suppression of autologous effector T-cell proliferation by Treg cell in coculture.The TNFR2+ expression on CD4+CD127lo/- T cells correlated with Treg cell-suppressive function (r = 0.63, P0.01). In receiver operating characteristic curves, percentage and absolute number of CD4+CD127lo/-TNFR2+ Treg cell predicted DGF from non-DGF (IGF + SGF) with area under the curves of 0.75 and 0.77, respectively, and also AKI (DGF + SGF) from IGF with area under the curves of 0.76 and 0.72, respectively (P0.01). Prediction of AKI (DGF + SGF) from IGF remained significant in multivariate logistic regression accounting for cold ischemic time, donor age, previous transplant, and pretransplant dialysis modality.Pretransplant recipient circulating CD4+CD127lo/-TNFR2+ Treg cell is potentially a simpler alternative to Treg cell function as a pretransplant recipient immune marker for AKI (DGF + SGF), independent from donor and organ procurement characteristics.

BACKGROUND Delayed graft function (DGF) and slow graft function (SGF) are a continuous spectrum of ischemia-reperfusion-related acute kidney injury (AKI) that increases the risk for acute rejection and graft loss after kidney transplantation. Regulatory T cells (Tregs) are critical in transplant tolerance and attenuate murine AKI. In this prospective observational cohort study, we evaluated whether pretransplantation peripheral blood recipient Treg frequency and suppressive function are predictors of DGF and SGF after kidney transplantation. METHODS Deceased donor kidney transplant recipients (n=53) were divided into AKI (n=37; DGF, n=10; SGF, n=27) and immediate graft function (n=16) groups. Pretransplantation peripheral blood CD4CD25FoxP3 Treg frequency was quantified by flow cytometry. Regulatory T-cell suppressive function was measured by suppression of autologous effector T-cell proliferation by Treg in co-culture. RESULTS Pretransplantation Treg suppressive function, but not frequency, was decreased in AKI recipients (P

A 67-year-old man known for metastatic colon cancer received treatment with oxaliplatin and developed severe acute kidney injury requiring dialysis. Renal biopsy revealed severe acute tubular necrosis. Acute kidney injury is a rare but severe adverse effect of oxaliplatin administration.

Background. A significant percentage of biopsies from stable, well-functioning renal allografts have histologic findings consistent with acute rejection or borderline rejection. The implication of this finding is not yet fully understood. We analyzed immune-activation gene transcripts in stable protocol biopsies to determine the extent of immunologic activity of graft-infiltrating cells in this setting. Histologic classification of the biopsies was based on the Banff criteria. To emphasize that the tissue samples were procured from grafts with no clinical evidence of impaired function, we interjected the term subclinical into the Banff terminology. This produced three histologic categories : normal, borderline subclinical rejection, and acute subclinical rejection. Methods. We used competitive template polymerase chain reaction techniques to quantify transcript amounts for the constant region of the T-cell receptor β chain; the cytokines, tumor necrosis factor a, interleukin (IL)-1β, transforming growth factor β, interferon γ, IL-2, IL-4, IL-10, and IL-15; and the cytotoxic T lymphocyte effector molecules, granzyme B, perforin, and Fas ligand. Results. We found that histologically normal biopsies were typically devoid of gene transcripts or had very low amounts. Conversely, biopsies with acute subclinical rejection by histologic examination had heightened amounts of transcripts for many of the genes assayed. Borderline subclinical rejection samples showed an intermediate amount of expression. Conclusions. These results demonstrate that histologic features of rejection are often accompanied by enhanced expression of pro-inflammatory gene transcripts, despite the absence of clinically overt graft dysfunction. As this state of subclinical rejection could prove detrimental to long-term graft function, a role for surveillance biopsies of stable grafts with intent to treat subclinical rejection should be considered.

Mutations in the PEX gene are responsible for X-linked hypophosphatemic rickets. To gain insight into the role of PEX in normal physiology we have cloned the human full-length cDNA and studied its tissue expression, subcellular localization, and peptidase activity. We show that the cDNA encodes a 749-amino acid protein structurally related to a family of neutral endopeptidases that include neprilysin as prototype. By Northern blot analysis, the size of the full-length PEXtranscript is 6.5 kilobases. PEX expression, as determined by semi-quantitative polymerase chain reaction, is high in bone and in tumor tissue associated with the paraneoplastic syndrome of renal phosphate wasting. PEX is glycosylated in the presence of canine microsomal membranes and partitions exclusively in the detergent phase from Triton X-114 extractions of transiently transfected COS cells. Immunofluorescence studies in A293 cells expressing PEX tagged with a c-myc epitope show a predominant cell-surface location for the protein with its COOH-terminal domain in the extracellular compartment, substantiating the assumption that PEX, like other members of the neutral endopeptidase family, is a type II integral membrane glycoprotein. Cell membranes from cultured COS cells transiently expressing PEX efficiently degrade exogenously added parathyroid hormone-derived peptides, demonstrating for the first time that recombinant PEX can function as an endopeptidase. PEX peptidase activity may provide a convenient target for pharmacological intervention in states of altered phosphate homeostasis and in metabolic bone diseases.

Background Recent studies have raised concern about the safety of erythropoiesis‐stimulating agents because of evidence of increased risk of hypertension and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. In the present study, we investigated the effects of recombinant human erythropoietin (EPO) on endothelial function of gluteal subcutaneous resistance arteries isolated from 17 stage 4 patients (estimated glomerular filtration rate 21.9±7.4 mL/min per 1.73 m2) aged 63±13 years. Methods and Results Arteries were mounted on a pressurized myograph. EPO impaired endothelium‐dependent relaxation in a concentration‐dependent manner. The maximal response to acetylcholine with EPO at 1, 10, and 20 IU/mL was reduced by 12%, 34%, and 43%, respectively, compared with the absence of EPO (P

Background Recent studies have raised concern about the safety of erythropoiesis‐stimulating agents because of evidence of increased risk of hypertension and cardiovascular morbidity and mortality in chronic kidney disease ( CKD ) patients. In the present study, we investigated the effects of recombinant human erythropoietin ( EPO ) on endothelial function of gluteal subcutaneous resistance arteries isolated from 17 stage 4 patients (estimated glomerular filtration rate 21.9±7.4 mL/min per 1.73 m 2 ) aged 63±13 years. Methods and Results Arteries were mounted on a pressurized myograph. EPO impaired endothelium‐dependent relaxation in a concentration‐dependent manner. The maximal response to acetylcholine with EPO at 1, 10, and 20 IU/mL was reduced by 12%, 34%, and 43%, respectively, compared with the absence of EPO ( P EPO ‐induced endothelial dysfunction was significantly associated with carotid stiffness and history of cardiovascular events. EPO had no effect on norepinephrine‐induced vasoconstriction or sodium nitroprusside–induced relaxation. ABT ‐627, an endothelin type A receptor antagonist, and tempol, a superoxide dismutase mimetic, partially reversed the altered endothelial function in the presence of EPO ( P EPO . Conclusions EPO alters endothelial function of resistance arteries in CKD patients via a mechanism involving in part oxidative stress and signaling through an endothelin type A receptor. EPO ‐induced endothelial dysfunction could contribute to deleterious effects of EPO described in large interventional trials.

Despite improving immunosuppressive protocols in renal transplantation, chronic allograft nephropathy (CAN) remains a major impediment to long-term graft survival. The optimal immunosuppressive regimen for a patient with CAN is unknown. The aim of this study is to evaluate the various immunosuppressive management strategies of biopsy-proven CAN and of chronic allograft dysfunction (CAD) (no biopsy). A systematic review of randomized trials (n = 12 trials with 635 patients) was conducted. Studies included patients who were >6 mo post-transplant. All patients were on a calcineurin inhibitor (CNI), most often cyclosporine, and were randomized to convert to mycophenolate mofetil (MMF), tacrolimus, or sirolimus (Rapa) or to add azathioprine, MMF or Rapa to their current regimen. Follow-up time was 6 to 36 mo. The outcome measures evaluated were renal function in 11 of 12 studies and repeat renal biopsy results in one study. The methodological quality scores of the trials were generally low, using the Jadad scale (median value 2/5). Results varied between studies but suggested that CNI withdrawal is safe and that conversion to MMF or Rapa may be beneficial. The incidence of adverse effects ranged from 0% to 68% between the studies, and medication withdrawal occurred in 0% to 24% of patients. The review did not result in a consensus regarding the management of CAN and CAD. Further studies are required to determine the best therapeutic option for patients with CAD and CAN.

Accelerated cardiovascular disease is a frequent complication of renal disease. Chronic kidney disease promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Furthermore, diabetic nephropathy is the leading cause of renal failure in developed countries. Together, hypertension, dyslipidemia, and diabetes are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis. Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in chronic kidney disease, which likely contributes through enhanced production of reactive oxygen species to the accelerated atherosclerosis observed in chronic kidney disease. Promoters of calcification are increased and inhibitors of calcification are reduced, which favors metastatic vascular calcification, an important participant in vascular injury associated with end-stage renal disease. Accelerated atherosclerosis will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease. Consequently, subjects with chronic renal failure are exposed to increased morbidity and mortality as a result of cardiovascular events. Prevention and treatment of cardiovascular disease are major considerations in the management of individuals with chronic kidney disease.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive metabolic disorder resulting in the overproduction of plasma oxalate. Although the enzymatic defect is in hepatocyte peroxisomes, uncontrolled levels of oxalate result in calcium oxalate deposition in multiple organs. Because the primary route of elimination of oxalate is renal excretion, high levels are found in urine, which results in supersaturation and crystal nucleation. Patients typically present with recurrent nephrolithiasis and nephrocalcinosis. If not diagnosed early, end-stage renal disease (ESRD) and systemic calcium oxalate deposition can occur. Once ESRD develops, intensive dialysis therapy is unable to keep pace with the high oxalate production, and the preferred therapeutic intervention is combined kidney-liver transplantation. Here, we report a young man with a history of recurrent nephrolithiasis who presented to us with ESRD and subsequently developed manifestations of systemic oxalosis. The diagnosis of PH1 must be considered in the differential diagnosis of patients presenting with ESRD with a history of recurrent nephrolithiasis. The diagnosis of PH1 is more challenging in patients with ESRD, for whom urinary oxalate levels are often normal or only modestly increased because of decreased glomerular filtration, and recurrent nephrolithiasis is no longer the dominant clinical feature.

Introduction Immunosuppressive agents must not only be effective in impairing the host's allo-immune response, but should also be selective in targeting only those elements of the immune system activated by the allograft. The fact that allo-activated T cells express surface protein molecules that are not typically present on resting T cells can be exploited to specifically target this population. Fas ligand is one such molecule whose cell surface expression on T cells is dramatically up-regulated upon activation. Methods We constructed a murine fusion protein by linking the extracellular domain of Fas to the Fc region of IgG2a. The rationale being to selectively target activated T cells via binding of its Fas moiety to cell surface Fas ligand, and then to allow the Fc moiety to invoke its usual effector mechanisms resulting in the destruction of the allo-activated T cell. Here, we describe the design and expression of Fas-IgG2a and characterize several key in vitro and in vivo properties of this fusion protein including its ability to impact on both cell-mediated immune responses and cellular apoptotic activity using a murine model of delayed-type hypersensitivity. Results In vitro, our Fas-IgG2a construct bound activated T cells via FasL and invoked cytotoxicity. In vivo, it demonstrated a prolonged half-life characteristic of an immunoglobulin-like molecule. Most significantly, it suppressed the cell-mediated immune response and diminished cellular apoptotic activity in lymphoid tissue in our murine model. Conclusion Fas-IgG2a is a novel agent for delivering target-specific immunosuppression with potential applicability in the transplant setting.