SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis.

The Hippo pathway nuclear effector Yes-associated protein (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1), driven by ERK1/2 and PI3K/AKT cascades, induced ER proteotoxic stress. To reduce this stress by reprogramming translation, the protein kinase R-like ER kinase-eukaryotic initiation factor 2α (PERK/eIF2α) arm of the integrated stress response (ISR) was activated. PERK-mediated phosphorylation of eIF2α drove the selective translation of activating transcription factor 4 (ATF4), potentiating YAP expression. In parallel, YAP underwent K63-linked polyubiquitination by SCF S-phase kinase-associated protein 2 (SKP2) E3 ubiquitin ligase, a Hippo-independent, nonproteolytic ubiquitination that enhances YAP nuclear trafficking and transcriptional activity in cancer cells. Defective ISR cellular adaptation to ER stress in eIF2α phosphorylation-deficient jck mice further augmented YAP-mediated transcriptional activity and renal cyst growth. Conversely, pharmacological tuning down of ER stress/ISR activity and SKP2 expression in jck mice by administration of tauroursodeoxycholic acid (TUDCA) or tolvaptan impeded these processes. Restoring ER homeostasis and/or interfering with the SKP2-YAP interaction represent potential therapeutic avenues for stemming the progression of renal cystogenesis.

Distinct transcriptomic profile of small arteries of hypertensive patients with chronic kidney disease identified miR-338-3p targeting GPX3 and PTPRS.

OBJECTIVE: 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. METHODS AND RESULTS: 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). CONCLUSION: 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.

Long-term Effects of a Brief Mindfulness Intervention Versus a Health Enhancement Program for Treating Depression and Anxiety in Patients Undergoing Hemodialysis: A Randomized Controlled Trial.

Background: Depression and anxiety affect approximately 50% of patients with kidney failure receiving hemodialysis and are associated with decreased quality of life and increased risk of hospitalization and mortality. A Brief Mindfulness Intervention (BMI) may be promising in treating depressive and anxiety symptoms in this population, but the long-term sustainability of the intervention's effects is unknown. Objective: We previously conducted a randomized controlled trial (RCT; n = 55) comparing an 8-week BMI with an active control (Health Enhancement Program [HEP]) for patients receiving dialysis, with depression and/or anxiety. Here, we examine the 6-month follow-up data to determine the long-term sustainability of BMI versus HEP in reducing (1) depressive symptoms, (2) anxiety symptoms, and (3) the efficacy of BMI versus HEP in reducing the likelihood of hospitalization. Design: In this study, we analyzed 6-month follow-up data from an 8-week assessor-blinded parallel RCT, which evaluated the efficacy of a BMI against an active control, HEP, in patients receiving hemodialysis with symptoms of depression and/or anxiety. Setting: The study took place at hemodialysis centers in 4 tertiary-care hospitals in Montreal, Canada. Participants: Participants included adults aged ≥18 years who were receiving in-center hemodialysis 3 times per week and had symptoms of depression and/or anxiety as indicated by a score ≥6 on the Patient Health Questionnaire-9 (PHQ-9) and/or the General Anxiety Disorder-7 (GAD-7). Methods: Participants were randomized to the treatment arm (BMI) or the active control arm (HEP) and completed assessments at baseline, 8 weeks, and 6-month follow-up. Depression was assessed using the PHQ-9, and anxiety was assessed by the GAD-7. Hospitalization rates were assessed using medical chart information. Results: We observed significant decrease in depression scores over 6 months in both BMI and HEP groups, with no significant difference between groups. Anxiety scores significantly decreased over 6 months, but only in the BMI group. Brief Mindfulness Intervention and Health Enhancement Program were comparable in terms of hospitalization rates. Limitations: The limitations of our study include the modest sample size and lack of a third arm such as a waitlist control. Conclusions: Our results suggest that the beneficial effects of BMI and HEP for improving mood disorder symptoms in patients receiving dialysis persist at 6-month follow-up. Both interventions showed sustained effects for depressive symptoms, but BMI may be more useful in this population given its efficacy in reducing anxiety symptoms as well. Trial registration: Prior to recruitment, the trial had been registered (ClinicalTrials.gov Identifier: NCT03406845).

Contexte: La dépression et l'anxiété touchent environ 50% des patients atteints d'insuffisance rénale sous hémodialyse et sont associées à une diminution de la qualité de vie et à un risque accru d'hospitalisation et de mortalité. Une brève intervention basée sur la pleine conscience pourrait s'avérer prometteuse pour le traitement des symptômes liés à l'anxiété et à la dépression dans cette population. On ignore toutefois la viabilité à long terme des effets d'une telle intervention. Objectifs: Nous avons précédemment mené un essai contrôlé randomisé (n = 55) comparant une brève intervention de pleine conscience (IPC) de huit semaines à un témoin actif (Programme d'amélioration de la santé [PAmS]) chez les patients sous dialyse présentant des symptômes de dépression et/ou d'anxiété. Nous examinons ici les données après six mois de suivi pour déterminer la viabilité à long terme de l'IPC par rapport au PAmS sur la réduction (1) des symptômes dépressifs, (2) des symptômes d'anxiété, et (3) l'efficacité de l'IPC par rapport au PAmS à réduire la probabilité d'hospitalisation. Type d'étude: Un essai contrôlé randomisé, d'une durée de huit semaines, mené en parallèle et en aveugle pour l'évaluateur, lequel évaluait l'efficacité d'une IPC par rapport au témoin actif (PAmS) chez les patients sous hémodialyse présentant des symptômes de dépression et/ou d'anxiété. Cadre: L'étude a eu lieu dans les centres d'hémodialyse de quatre hôpitaux de soins tertiaires de Montréal (Canada). Participants: Des adultes qui recevaient des traitements d'hémodialyse en centre 3x/semaine et qui présentaient des symptômes de dépression et/ou d'anxiété tels que définis par un score ≥6 au questionnaire sur la santé des patients (PHQ-9) et/ou sur le trouble général d'anxiété-7 (GAD-7). Méthodologie: Les participants ont été répartis aléatoirement dans le groupe de traitement (IPC) ou le groupe témoin actif (PAmS) et ont répondu aux questionnaires au début de l'étude, après huit semaines et après six mois de suivi. La dépression a été évaluée à l'aide du PHQ-9 et l'anxiété par le GAD-7. Les taux d'hospitalisation ont été évalués à l'aide des dossiers médicaux. Résultats: Nous avons observé une diminution significative des scores de dépression sur six mois dans les groupes IPC et PAmS, sans différence significative entre les groupes. Seul le groupe IPC a montré une diminution significative des scores d'anxiété sur six mois. Les taux d'hospitalisation étaient comparables dans les deux groupes. Limites: Taille modeste de l'échantillon et absence d'un troisième bras tel un groupe témoin constitué de patients sur une liste d'attente. Conclusion: Nos résultats suggèrent que les effets bénéfiques de l'IPC et du PAmS sur les symptômes des troubles de l'humeur des patients sous dialyse persistent après six mois de suivi. Les deux interventions ont montré des effets durables sur les symptômes dépressifs, mais l'IPC pourrait s'avérer plus pertinente dans cette population puisqu'elle a également montré une efficacité à réduire les symptômes d'anxiété. Enregistrement de l'essai: L'essai avait été enregistré avant le recrutement (ClinicalTrials.gov Identificateur : NCT03406845).

Do Brief Mindfulness Interventions (BMI) and Health Enhancement Programs (HEP) Improve Sleep in Patients in Hemodialysis with Depression and Anxiety?

(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.

Brief Mindfulness Intervention vs. Health Enhancement Program for Patients Undergoing Dialysis: A Randomized Controlled Trial.

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.

Corrigendum to "A Case of Severe Acute Kidney Injury Exacerbated by Canagliflozin in a Patient with Type 2 Diabetes".

[This corrects the article DOI: 10.1155/2019/8639629.].

Could symptom burden predict subsequent healthcare use in patients with end stage kidney disease on hemodialysis care? A prospective, preliminary study.

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.

Circulating let-7g-5p and miR-191-5p Are Independent Predictors of Chronic Kidney Disease in Hypertensive Patients.

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 <0.1. DE miRNAs were identified uniquely associated with HTN, MetS, or CKD. However, only 2 downregulated DE miRNAs (let-7g-5p and miR-191-5p) could be validated by reverse transcription-quantitative PCR. Let-7g-5p was associated with large vessel stiffening, miR-191-5p with MetS, and both miRNAs with estimated glomerular filtration rate (eGFR) and neutrophil and lymphocyte fraction or number and neutrophil-to-lymphocyte ratio. Using the whole population, stepwise multiple linear regression generated a model showing that let-7g-5p, miR-191-5p, and urinary albumin/creatinine ratio predicted eGFR with an adjusted R2 of 0.46 (P = 8.5e-7). 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.

A Case of Severe Acute Kidney Injury Exacerbated by Canagliflozin in a Patient with Type 2 Diabetes.

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.

Psychosocial Distress and Health Service Utilization in Patients Undergoing Hemodialysis: A Prospective Study.

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.

Angiotensin-Converting Enzyme Inhibitors vs. Angiotensin Receptor Blockers for the Treatment of Hypertension in Adults With Type 2 Diabetes: Why We Favour Angiotensin Receptor Blockers.

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.

Defective interplay between mTORC1 activity and endoplasmic reticulum stress-unfolded protein response in uremic vascular calcification.

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.

Warfarin anticoagulation in hemodialysis patients with atrial fibrillation: comparison of nephrologist-led and anticoagulation clinic-led management.

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.

Brief Mindfulness Meditation for Depression and Anxiety Symptoms in Patients Undergoing Hemodialysis: A Pilot Feasibility Study.

BACKGROUND AND OBJECTIVES: Up to 50% of patients undergoing hemodialysis suffer from symptoms of depression and/or anxiety. Access to traditional pharmacotherapies and psychotherapies for depression or anxiety in this patient population has been inadequate. The objective of this study was to investigate the feasibility and effectiveness of brief mindfulness meditation intervention for patients on hemodialysis with depression and anxiety symptoms. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study was a randomized, controlled, assessor-blinded trial conducted in an urban hemodialysis unit. Forty-one patients were randomly assigned to intervention (n=21) and treatment-as-usual (n=20) groups. The intervention group received an 8-week individual chairside meditation intervention lasting 10-15 minutes, three times a week during hemodialysis. Feasibility outcomes were primarily assessed: enrollment rates, intervention completion rates, and intervention tolerability. Symptoms of depression and anxiety were measured using the Patient Health Questionnaire (PHQ-9) and the General Anxiety Disorder-7 (GAD-7). RESULTS: Of those deemed eligible for the study, 67% enrolled (41 of 61). Of the participants randomized to the intervention group, 71% completed the study, with meditation being well tolerated (median rating of 8 of 10 in a Likert scale; interquartile range=10-5 of 10). Barriers to intervention delivery included frequent hemodialysis shift changes, interruptions by staff or alarms, space constraints, fluctuating participant medical status, and participant fatigue. Meditation was associated with subjective benefits but no statistically significant effect on depression scores (change in PHQ-9, -3.0±3.9 in the intervention group versus -2.0±4.7 in controls; P=0.45) or anxiety scores (change in GAD-7, -0.9±4.6 versus -0.8±4.8; P=0.91). CONCLUSIONS: On the basis of the results of this study, mindfulness meditation appears to be feasible and well tolerated in patients on hemodialysis with anxiety and depression symptoms. The study did not reveal significant effects of the interventions on depression and anxiety scores. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_10_12_CJASNPodcast_17_12_.mp3.

Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients.

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<0.001). Trough levels increased from 45 to 132 ng/ml (P<0.001). On day 9, after a 2.5-mg dose, apixaban levels were monitored hourly during dialysis. Only 4% of the drug was removed. After a 5-day washout period, five patients received 5 mg apixaban twice daily for 8 days. The area under the concentration-time curve further increased to 6045 ng h/ml (P=0.03), and trough levels increased to 218 ng/ml (P=0.03), above the 90th percentile for the 5-mg dose in patients with preserved renal function. Apixaban 2.5 mg twice daily in patients on hemodialysis resulted in drug exposure comparable with that of the standard dose (5 mg twice daily) in patients with preserved renal function and might be a reasonable alternative to warfarin for stroke prevention in patients on dialysis. Apixaban 5 mg twice daily led to supratherapeutic levels in patients on hemodialysis and should be avoided.

Pretransplant Recipient Circulating CD4+CD127lo/- Tumor Necrosis Factor Receptor 2+ Regulatory T Cells: A Surrogate of Regulatory T Cell-Suppressive Function and Predictor of Delayed and Slow Graft Function After Kidney Transplantation.

BACKGROUND: 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. METHODS: 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. RESULTS: The TNFR2+ expression on CD4+CD127lo/- T cells correlated with Treg cell-suppressive function (r = 0.63, P < 0.01). 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 (P < 0.01). 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. CONCLUSIONS: 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.

The relationship between proton pump inhibitor use and serum magnesium concentration among hemodialysis patients: a cross-sectional study.

BACKGROUND: Observational data suggest that serum magnesium (Mg) concentration is inversely related to vascular calcification and hyperparathyroidism among patients with end-stage renal disease (ESRD). In recent years, there have been several case reports of hypomagnesemia due to use of proton-pump inhibitors (PPI), with the hypomagnesemia attributed to inappropriate gastrointestinal (GI) Mg loss. We hypothesized that the tendency to GI Mg loss is more common than is currently reported. Since patients with ESRD have little to no renal Mg loss to affect serum Mg concentration, dialysis patients are an interesting population in whom to study the relationship between PPI use and serum Mg levels. METHODS: Using a single-center cross-sectional design, we studied 155 prevalent hemodialysis (HD) patients. Serum Mg concentration for each patient was determined based on the mean of 3 consecutive serum Mg levels drawn at 6 week intervals. PPI use at the time of the blood tests was documented. The relationship between PPI use and Mg concentration was determined in unadjusted analyses, as well as after adjustment for age, gender, race, cause of ESRD, diabetes, time on HD and dialysate Mg concentration. RESULTS: 55 % of patients were on PPIs at the time of the study. The majority of patients (62 %) used a dialysate Mg (in mmol/L) of 0.5, and the remainder (38 %) used a dialysate Mg of 0.375. Serum Mg levels were significantly lower among PPI users vs. non-users (0.93 vs. 1.02 mmol/L, p < 0.001). This finding persisted after stratifying for dialysate Mg concentration, and after multivariable adjustment (p < 0.001). In addition, more PPI users vs. non-users had a Mg level < 1 mmol/L (79 % vs. 43 %) and a Mg level < 0.8 mmol/L (16 % vs. 4 %). There was a non-significant trend toward increased time on PPI being associated with lower serum Mg levels (p = 0.067). CONCLUSION: Among HD patients, PPI users have lower serum Mg levels as compared with non-users. Further research is required to determine whether the magnitude of change in Mg levels among PPI users is associated with adverse outcomes.

Pretransplantation recipient regulatory T cell suppressive function predicts delayed and slow graft function after kidney transplantation.

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<0.01). In univariate and multivariate analyses accounting for the effects of cold ischemic time and donor age, Treg suppressive function discriminated DGF from immediate graft function recipients in multinomial logistic regression (odds ratio, 0.77; P<0.01), accurately predicted AKI in receiver operating characteristic curve (area under the curve, 0.82; P<0.01), and predicted 14-day estimated glomerular filtration rate in linear regression (P<0.01). CONCLUSION: Our results indicate that recipient peripheral blood Treg suppressive function is a potential independent pretransplantation predictor of DGF and SGF.