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Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Because many genes associate with DKD, multiomics approaches were used to narrow the list of functional genes, gene products, and related pathways providing insights into the pathophysiological mechanisms of DKD. The Kidney Precision Medicine Project human kidney single-cell RNA-sequencing (scRNA-seq) data set and Mendeley Data on human kidney cortex biopsy proteomics were used. The R package Seurat was used to analyze scRNA-seq data and data from a subset of proximal tubule cells. PathfindR was applied for pathway analysis in cell type-specific differentially expressed genes and the R limma package was used to analyze differential protein expression in kidney cortex. A total of 790 differentially expressed genes were identified in proximal tubule cells, including 530 upregulated and 260 downregulated transcripts. Compared with differentially expressed proteins, 24 genes or proteins were in common. An integrated analysis combining protein quantitative trait loci, genome-wide association study hits (namely, estimated glomerular filtration rate), and a plasma metabolomics analysis was performed using baseline metabolites predictive of DKD progression in our longitudinal Diabetes Heart Study samples. The aldo-keto reductase family 1 member A1 gene (AKR1A1) was revealed as a potential molecular hub for DKD cellular dysfunction in several cross-linked pathways featured by deficiency of this enzyme., (© 2024 by the American Diabetes Association.)

Rationale and Objective: This study aimed to develop a cosmesis scale to evaluate the cosmetic appearance of hemodialysis (HD) arteriovenous (AV) accesses from the perspective of the patient and clinician, which could be incorporated into clinical trials., Study Design: Using a modified Delphi process, two AV access cosmesis scale (AVACS) components were developed in a four-round Delphi panel consisting of two surveys and two consensus meetings with two rounds of patient consultation., Setting and Participants: The Delphi panel consisted of 15 voting members including five interventional or general nephrologists, five vascular surgeons, three interventional radiologists, and two vascular access nurse coordinators. Four patients experienced with vascular access were involved in patient question development., Analytical Approach: For a component to be included in the AVACS, it had to meet the prespecified panel consensus agreement of ⩾70%., Results: The clinician component of the AVACS includes nine questions on the following AV access features: scarring, skin discoloration, aneurysm/pseudoaneurysms and megafistula appearance. The patient component includes six questions about future vascular access decisions, interference with work or leisure activities, clothing choices, self-consciousness or attractiveness, emotional impact, and overall appearance., Limitations: Delphi panel methods are subjective by design, but with expert clinical opinion are used to develop classification systems and outcome measures. The developed scale requires further validation testing but is available for clinical trial use., Conclusions: While safety and efficacy are the primary concerns when evaluating AV access for HD, cosmesis is an important component of the ESKD patient experience. The AVACS has been designed to assess this important domain; it can be used to facilitate patient care and education about vascular access choice and maintenance. AVACS can also be used to inform future research on developing new techniques for AV access creation and maintenance, particularly as relates to AV access cosmesis., Competing Interests: Declaration of Conflicting InterestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare that they have no conflicts of interest regarding patents or royalties, stock/stock options, or first-degree relatives with any of these relationships related to this work. No reimbursement was received for the development of the manuscript.DR, VN, MM, CR, ED, CG, TV, SH, PB, LD and patients CS, DDR, FM, and MB (see acknowledgements) received remuneration from Becton Dickinson (BD) for their participation in the Delphi process.GW, AH, and NF are employees of CRG-EVERSANA Canada Inc., which was contracted by BD to facilitate the Delphi panel process and analyze the results.EK and DC are employees of the American Association of Kidney Patients (AAKP) which was contracted by BD to advise on patient input and recruited the Patient Ambassadors.DR is a consultant for BD and Gore Medical. VN is a consultant for the NACCME – Moderator for AV Access Webcast, supported by an educational grant from Medtronic. SH is a consultant/speaker for BD, Merit Medical, Medtronic, and Gore Medical. ED is a consultant for WL Gore, Angiodynamics, and 3M/KCI. ED is a scientific advisor for Boston Scientific. TY is a consultant for BD, WL Gore and Merit Medical and a scientific advisory board member of BD and Medtronic. CK is a consultant for BD and ACI/Humacyte and advisory board member for Boston Scientific. CL is a consultant for BD, Gore, and Medtronic.Other ConflictsED, KW, and TY are authors and ED is an editor for UpToDate.

Background: Most patients starting chronic in-center hemodialysis (HD) receive conventional hemodialysis (CHD) with three sessions per week targeting specific biochemical clearance. Observational studies suggest that patients with residual kidney function can safely be treated with incremental prescriptions of HD, starting with less frequent sessions and later adjusting to thrice-weekly HD. This trial aims to show objectively that clinically matched incremental HD (CMIHD) is non-inferior to CHD in eligible patients., Methods: An unblinded, parallel-group, randomized controlled trial will be conducted across diverse healthcare systems and dialysis organizations in the USA. Adult patients initiating chronic hemodialysis (HD) at participating centers will be screened. Eligibility criteria include receipt of fewer than 18 treatments of HD and residual kidney function defined as kidney urea clearance ≥3.5 mL/min/1.73 m 2 and urine output ≥500 mL/24 h. The 1:1 randomization, stratified by site and dialysis vascular access type, assigns patients to either CMIHD (intervention group) or CHD (control group). The CMIHD group will be treated with twice-weekly HD and adjuvant pharmacologic therapy (i.e., oral loop diuretics, sodium bicarbonate, and potassium binders). The CHD group will receive thrice-weekly HD according to usual care. Throughout the study, patients undergo timed urine collection and fill out questionnaires. CMIHD will progress to thrice-weekly HD based on clinical manifestations or changes in residual kidney function. Caregivers of enrolled patients are invited to complete semi-annual questionnaires. The primary outcome is a composite of patients' all-cause death, hospitalizations, or emergency department visits at 2 years. Secondary outcomes include patient- and caregiver-reported outcomes. We aim to enroll 350 patients, which provides ≥85% power to detect an incidence rate ratio (IRR) of 0.9 between CMIHD and CHD with an IRR non-inferiority of 1.20 (α = 0.025, one-tailed test, 20% dropout rate, average of 2.06 years of HD per patient participant), and 150 caregiver participants (of enrolled patients)., Discussion: Our proposal challenges the status quo of HD care delivery. Our overarching hypothesis posits that CMIHD is non-inferior to CHD. If successful, the results will positively impact one of the highest-burdened patient populations and their caregivers., Trial Registration: Clinicaltrials.gov NCT05828823. Registered on 25 April 2023., (© 2024. The Author(s).)

Individuals afflicted with advanced kidney dysfunction who require dialysis for medical management exhibit different degrees of native kidney function, called residual kidney function (RKF), ranging from nil to appreciable levels. The primary focus of this manuscript is to delve into the concept of RKF, a pivotal yet under-represented topic in nephrology. To begin, we unpack the definition and intrinsic nature of RKF. We then juxtapose the efficiency of RKF against that of hemodialysis in preserving homeostatic equilibrium and facilitating physiological functions. Given the complex interplay of RKF and overall patient health, we shed light on the extent of its influence on patient outcomes, particularly in those living with advanced kidney dysfunction and on dialysis. This manuscript subsequently presents methodologies and measures to assess RKF, concluding with the potential benefits of targeted interventions aimed at preserving RKF., Competing Interests: The authors declare no conflicts of interest. The views, statements, and opinions presented are solely the responsibility of the author(s) and do not necessarily represent the views of PCORI or NIH.

Introduction: Longitudinal changes in residual kidney function have not been well-examined in patients starting chronic hemodialysis (HD)., Methods: We analyzed urine volume and kidney solute clearances from timed urine collections and corresponding plasma samples from 42 patients randomized to incremental HD ( n  = 21) and conventional HD ( n  = 21) in the TwoPlus pilot study. Samples were collected before HD initiation (baseline); and at 6, 12, 24, and 48 weeks. We assessed temporal trends in urine volume, kidney urea and creatinine clearance, and correlations between urine volume and kidney solute clearance., Results: Residual kidney function parameters in all patients declined over time; the pattern of decline differed between urine volume and kidney solute clearances. Urine volume declined at a steady rate with median (quartile 1, quartile 3) percentage change relative to baseline of -10% (-36 to 29) at week 6 and -47% (-76 to 5) by week 48. Kidney urea and creatinine clearances exhibited a larger decline than urine volume at week 6, -32% (-61 to 8) and -47% (-57 to -20), respectively. The rate of decline subsequently slowed, reaching about 61% decline for both solutes by week 48. Conventional HD demonstrated larger declines in urine volume and kidney urea clearance than incremental HD at week 6. Urine volume showed moderate correlation with urea (R = 0.47) and weaker correlation with creatinine (R = 0.34)., Conclusion: Despite gradual decrement in urine volume and kidney solute clearances, residual kidney function persists nearly 1 year after HD initiation. This knowledge could motivate increased practice of individualizing HD prescriptions by incorporating residual kidney function., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Franco Casino and Mariana Murea discuss today's knowledge about the 'incremental dialysis' concept. Franco Casino frames the problem by saying that, in the presence of substantial residual kidney function, kidney replacement therapy can begin with low doses and/or frequencies, to be gradually increased to compensate for any subsequent losses of residual kidney function, keeping the total clearance above the minimum levels of adequacy. He remarks that studies so far have documented that this approach is safe. He recognizes that adequate randomized controlled trials (RCTs) are necessary to confirm the safety and simplify and standardize the practical aspects of this approach. Mariana Murea objects that most of the evidence gathered so far primarily derives from retrospective and observational studies, which can be influenced by socioeconomic constraints. She argues for the need for RCTs to provide compelling empirical evidence on the efficacy of incremental dialysis. Nephrologists are still reluctant to adopt this approach for various reasons, including unfamiliarity with the method, lack of practical guidance and financial disincentives. Several countries have ongoing or planned RCTs comparing incremental dialysis with conventional dialysis. These trials can shift the haemodialysis paradigm if they validate the safety and effectiveness of this approach. The moderators believe that the results of ongoing trials must be carefully interpreted, and further validation may be needed across different patient populations or healthcare settings. The ultimate goal is to gather robust evidence that could lead to widespread adoption of incremental haemodialysis, optimizing treatment, reducing overtreatment, preserving resources and improving patients' quality of life., Competing Interests: J.F. is the Editor-in-Chief of CKJ. C.Z. is member of the Editorial Board of CKJ., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Clinicians and patients are guided by observational studies to make one of the most consequential decisions for patients with advanced kidney disease: the selection of the "right" hemodialysis vascular access. More than a decade ago, a call for randomized clinical trials was made to equitably compare clinical outcomes between arteriovenous (AV) fistulas (AVFs) and AV grafts (AVGs). Mounting evidence suggests that trade-offs between AVF- and AVGrelated outcomes are context dependent. In this article, we summarize four streams of evidence that collectively underpin the burden of equipoise between the two types of AV access in older adults with comorbidities who are on hemodialysis with a central venous catheter.

Background: Treatment of end-stage kidney disease (ESKD) with hemodialysis requires surgical creation of an arteriovenous (AV) vascular access-fistula (AVF) or graft (AVG)-to avoid (or limit) the use of a central venous catheter (CVC). AVFs have long been considered the first-line vascular access option, with AVGs as second best. Recent studies have suggested that, in older adults, AVGs may be a better strategy than AVFs. Lacking evidence from well-powered randomized clinical trials, integration of these results into clinical decision making is challenging. The main objective of the AV Access Study is to compare, between the two types of AV access, clinical outcomes that are important to patients, physicians, and policy makers., Methods: This is a prospective, multicenter, randomized controlled trial in adults ≥ 60 years old receiving chronic hemodialysis via a CVC. Eligible participants must have co-existing cardiovascular disease, peripheral arterial disease, and/or diabetes mellitus; and vascular anatomy suitable for placement of either type of AV access. Participants are randomized, in a 1:1 ratio, to a strategy of AVG or AVF creation. An estimated 262 participants will be recruited across 7 healthcare systems, with average follow-up of 2 years. Questionnaires will be administered at baseline and semi-annually. The primary outcome is the rate of CVC-free days per 100 patient-days. The primary safety outcome is the cumulative incidence of vascular access (CVC or AV access)-related severe infections-defined as access infections that lead to hospitalization or death. Secondary outcomes include access-related healthcare costs and patients' experiences with vascular access care between the two treatment groups., Discussion: In the absence of studies using robust and unbiased research methodology to address vascular access care for hemodialysis patients, clinical decisions are limited to inferences from observational studies. The goal of the AV Access Study is to generate evidence to optimize vascular access care, based on objective, age-specific criteria, while incorporating goals of care and patient preference for vascular access type in clinical decision-making., Trial Registration: This study is being conducted in accordance with the tenets of the Helsinki Declaration, and has been approved by the central institutional review board (IRB) of Wake Forest University Health Sciences (approval number: 00069593) and local IRB of each participating clinical center; and was registered on Nov 27, 2020, at ClinicalTrials.gov (NCT04646226)., (© 2023. The Author(s).)

Background: Autogenous arteriovenous fistula (AVF) remains the standard of hemodialysis (HD) access; however, it cannot be reasonably obtained in all patients. For patients with contraindications to AVFs, prosthetic arteriovenous graft (AVG) remains an alternative. AVGs are plagued by high failure rates; however, there is a paucity of literature examining this. This study aims to examine a single-center review of outcomes of forearm loop AVGs in patients requiring HD access., Methods: A single institution, retrospective chart review was completed from 2012 to 2019, including demographics, end-stage renal disease etiology, brachial vessel diameters, and comorbidities. Logistic regression and Cox proportional hazard models were evaluated. Outcomes were defined as primary patency (time elapsed from graft creation until it was utilized as the patient's primary access), primary-assisted patency (time from primary access to intervention to maintain patency), and functional patency (time from graft placement until graft failure). Additionally, multinomial regression models were used to evaluate associations with categorical number of required interventions., Results: Ninety-eight patients [mean age 61.8 (13.9) years, 42.9% female] were identified as having brachial artery to brachial vein AVG creation during the study period, of which 75% achieved primary patency. Primary-assisted patency was 0.36 [standard error (SE) 0.07] at 6 months and 0.12 (SE 0.05) at 1 year. Functional patency was 0.75 (SE 0.07) at 6 months and 0.43 (SE 0.09) at 1 year. No association between preoperative vessel diameters and primary-assisted or functional patency was observed. Interestingly, there was a significant negative association between previous ipsilateral access and achievement of primary patency with a 60% decrease in odds of achieving primary patency in patients with previous ipsilateral access [odds ratio 0.4, 95% confidence interval (CI) 0.1-0.9, P = 0.03]. There was also noted to be a significant association between the presence of an ipsilateral catheter and increased risk of subsequent abandonment of the AVG (hazard ratio 2.6, 95% CI 1.1-5.8, P = 0.02)., Conclusions: Prosthetic forearm loop AVGs remain hindered in their utility as they show high rates of graft failure within a year of creation. A significant patient-specific factor leading to this was not clearly demonstrated. As guidelines change regarding the nature of dialysis access for patients on HD, these results draw into question the utility of prosthetic forearm loop grafts in patients requiring long-term HD access., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Physical and emotional symptoms are prevalent in patients with kidney-dysfunction requiring dialysis (KDRD) and the rigors of thrice-weekly hemodialysis (HD) may contribute to deteriorated health-related quality of life. Less intensive HD schedules might be associated with lower symptom and/or emotional burden., Methods: The TWOPLUS Pilot study was an individually-randomized trial conducted at 14 dialysis units, with the primary goal to assess feasibility and safety. Patients with incident KDRD and residual kidney function were assigned to incremental HD start (twice-weekly HD for 6 weeks followed by thrice-weekly HD) vs conventional HD (thrice-weekly HD). In exploratory analyses, we compared the two treatment groups with respect to three patient-reported outcomes measures. We analyzed the change from baseline in the score on Dialysis Symptom Index (DSI, range 0-150), Generalized Anxiety Disorder-7 (GAD-7, range 0-21), and Patient Health Questionnaire-9 (PHQ-9, range 0-27) at 6 (n = 20 in each treatment group) and 12 weeks (n = 21); with lower scores denoting lower symptom burden. Analyses were adjusted for age, race, gender, baseline urine volume, diabetes mellitus, and malignancy. Participants' views on the intervention were sought using a Patient Feedback Questionnaire (n = 14 in incremental and n = 15 in conventional group)., Results: The change from baseline to week 6 in estimated mean score (standard error; P value) in the incremental and conventional group was - 9.7 (4.8; P = 0.05) and - 13.8 (5.0; P = 0.009) for DSI; - 1.9 (1.0; P = 0.07) and - 1.5 (1.4; P = 0.31) for GAD-7; and - 2.5 (1.1; P = 0.03) and - 3.5 (1.5; P = 0.02) for PHQ-9, respectively. Corresponding changes from week 6 to week 12 were - 3.1 (3.2; P = 0.34) and - 2.4 (5.5; P = 0.67) in DSI score; 0.5 (0.6; P = 0.46) and 0.1 (0.6; P = 0.87) in GAD-7 score; and - 0.3 (0.6; P = 0.70) and - 0.5 (0.6; P = 0.47) in PHQ-9 score, respectively. Majority of respondents felt their healthcare was not jeopardized and expressed their motivation for study participation was to help advance the care of patients with KDRD., Conclusions: This study suggests a possible mitigating effect of twice-weekly HD start on symptoms of anxiety and depression at transition from pre-dialysis to KDRD. Larger clinical trials are required to rigorously test clinically-matched incrementally-prescribed HD across diverse organizations and patient populations., Trial Registration: Registered at ClinicalTrials.gov with study identifier NCT03740048, registration date 14/11/2018., (© 2022. The Author(s).)

Rationale & Objective: Thrice-weekly hemodialysis (HD) is the most common treatment modality for kidney failure in the United States. We conducted a pilot study to assess the feasibility and safety of incremental-start HD in patients beginning maintenance HD., Study Design: Pilot study., Setting & Participants: Adults with estimated glomerular filtration rate (eGFR) ≥5 mL/min/1.73 m 2 and urine volume ≥500 mL/d beginning maintenance HD at 14 outpatient dialysis units., Exposure: Randomized allocation (1:1 ratio) to twice-weekly HD and adjuvant pharmacologic therapy for 6 weeks followed by thrice-weekly HD (incremental HD group) or thrice-weekly HD (conventional HD group)., Outcome: The primary outcome was feasibility. Secondary outcomes included changes in urine volume and solute clearance., Results: Of 77 patients invited to participate, 51 consented to do so, representing 66% of eligible patients. We randomized 23 patients to the incremental HD group and 25 patients to the conventional HD group. Protocol-based loop diuretics, sodium bicarbonate, and patiromer were prescribed to 100%, 39%, and 17% of patients on twice-weekly HD, respectively. At a mean follow-up of 281.9 days, participant adherence was 96% to the HD schedule (22 of 23 and 24 of 25 in the incremental and conventional groups, respectively) and 100% in both groups to serial timed urine collection. The incidence rate ratio for all-cause hospitalization was 0.31 (95% CI, 0.08-1.17); and 7 deaths were recorded (1 in the incremental and 6 in the conventional group). At week 24, the incremental HD group had lower declines in urine volume (a difference of 51.0 [95% CI, -0.7 to 102.8] percentage points) and in the averaged urea and creatinine clearances (a difference of 57.9 [95% CI, -22.6 to 138.4] percentage points)., Limitations: Small sample size, time-limited twice-weekly HD., Conclusions: It is feasible to enroll patients beginning maintenance HD into a randomized study of incremental-start HD with adjuvant pharmacotherapy who adhere to the study protocol during follow-up. Larger multicenter clinical trials are indicated to determine the efficacy and safety of incremental HD with longer twice-weekly HD periods., Funding: Funding was provided by Vifor Inc., Trial Registration: Registered at ClinicalTrials.gov, identifier NCT03740048., (Copyright © 2022. Published by Elsevier Inc.)

Chronic kidney disease (CKD) confers a high burden of uremic symptoms that may be underrecognized, underdiagnosed, and undertreated. Unpleasant symptoms, such as CKD-associated pruritus and emotional/psychological distress, often occur within symptom clusters, and treating 1 symptom may potentially alleviate other symptoms in that cluster. The Living Well with Kidney Disease and Effective Symptom Management Consensus Conference convened health experts and leaders of kidney advocacy groups and kidney networks worldwide to discuss the effects of unpleasant symptoms related to CKD on the health and well-being of those affected, and to consider strategies for optimal symptom management. Optimizing symptom management is a cornerstone of conservative and preservative management which aim to prevent or delay dialysis initiation. In persons with kidney dysfunction requiring dialysis (KDRD), incremental transition to dialysis and home dialysis modalities offer personalized approaches. KDRD is proposed as the preferred term given the negative connotations of "failure" as a kidney descriptor, and the success stories in CKD journeys. Engaging persons with CKD to identify and prioritize their personal values and individual needs must be central to ensure their active participation in CKD management, including KDRD. Person-centered communication and care are required to ensure diversity, equity, and inclusion; education/awareness that considers the health literacy of persons with CKD; and shared decision-making among the person with CKD, care partners, and providers. By putting the needs of people with CKD, including effective symptom management, at the center of their treatment, CKD can be optimally treated in a way that aligns with their goals., (© 2022 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

Some randomized controlled trials (RCTs) have sought to determine whether different dialysis techniques, dialysis doses and frequencies of treatment are able to improve clinical outcomes in end-stage kidney disease (ESKD). Virtually all of these RCTs were enacted on the premise that 'more' haemodialysis might improve clinical outcomes compared to 'conventional' haemodialysis. Aim of the present narrative review was to analyse these landmark RCTs by posing the following question: were their intervention strategies (i.e., earlier dialysis start, higher haemodialysis dose, intensive haemodialysis, increase in convective transport, starting haemodialysis with three sessions per week) able to improve clinical outcomes? The answer is no. There are at least two main reasons why many RCTs have failed to demonstrate the expected benefits thus far: (1) in general, RCTs included relatively small cohorts and short follow-ups, thus producing low event rates and limited statistical power; (2) the designs of these studies did not take into account that ESKD does not result from a single disease entity: it is a collection of different diseases and subtypes of kidney dysfunction. Patients with advanced kidney failure requiring dialysis treatment differ on a multitude of levels including residual kidney function, biochemical parameters (e.g., acid base balance, serum electrolytes, mineral and bone disorder), and volume overload. In conclusion, the different intervention strategies of the RCTs herein reviewed were not able to improve clinical outcomes of ESKD patients. Higher quality studies are needed to guide patients and clinicians in the decision-making process. Future RCTs should account for the heterogeneity of patients when considering inclusion/exclusion criteria and study design, and should a priori consider subgroup analyses to highlight specific subgroups that can benefit most from a particular intervention., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Staging to capture kidney function and pathophysiologic processes according to severity is widely used in chronic kidney disease or acute kidney injury not requiring dialysis. Yet the diagnosis of "end-stage kidney disease" (ESKD) considers patients as a single homogeneous group, with negligible kidney function, in need of kidney replacement therapy. Herein, we review the evidence behind the heterogeneous nature of ESKD and discuss potential benefits of recasting the terminology used to describe advanced kidney dysfunction from a monolithic entity to a disease with stages of ascending severity. We consider kidney assistance therapy in lieu of kidney replacement therapy to better reconcile all available types of therapy for advanced kidney failure including dietary intervention, kidney transplantation, and dialysis therapy at varied schedules. The lexicon "kidney dysfunction requiring dialysis" (KDRD) with stages of ascending severity based on levels of residual kidney function (RKF)-that is, renal urea clearance-and manifestations related to uremia, fluid status, and other abnormalities is discussed. Subtyping KDRD by levels of RKF could advance dialysis therapy as a form of kidney assistance therapy adjusted based on RKF and clinical symptoms. We focus on intermittent hemodialysis and underscore the need to personalize dialysis treatments and improve characterization of patients included in clinical trials., (© 2021 Wiley Periodicals LLC.)

Purpose of Review: Advanced kidney failure requiring dialysis, commonly labeled end-stage kidney disease or chronic kidney disease stage 5D, is a heterogeneous syndrome -a key reason that may explain why: treating advanced kidney dysfunction is challenging and many clinical trials involving patients on dialysis have failed, thus far. Treatment with dialytic techniques - of which maintenance thrice-weekly hemodialysis is most commonly used - is broadly named kidney 'replacement' therapy, a term that casts the perception of a priori abandonment of intrinsic kidney function and subsumes patients into a single, homogeneous group., Recent Findings: Patients with advanced kidney failure necessitating dialytic therapy may have ongoing endogenous kidney function, and differ in their clinical manifestations and needs. Different terminology, for example, kidney dysfunction requiring dialysis (KDRD) with stages of progressive severity could better capture the range of phenotypes of patients who require kidney 'assistance' therapy., Summary: Classifying patients with KDRD based on objective, quantitative levels of endogenous kidney function, as well as patient-reported symptoms and quality of life, would facilitate hemodialysis prescriptions tailored to level of kidney dysfunction, clinical needs, and personal priorities. Such classification would encourage clinicians to move toward personalized, physiological, and adaptive approach to hemodialysis therapy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Shared decision-making (SDM) is a process of collaborative deliberation in the dyadic patient-physician interaction whereby physicians inform the patients about the pros and cons of all available treatment options and reach an agreement with the patients on their preferred treatment plan. In hemodialysis vascular access practice, SDM advocates a deliberative approach based on the existence of reasonable alternatives-that is, arteriovenous fistula, arteriovenous graft, and central venous catheter-so that patients are able to form and share preferences about access options. In spite of its ethical imperative, SDM is not broadly applied in hemodialysis vascular access planning. Physicians and surgeons commonly deliver prescriptive fistula-centered recommendations concerning the approach to vascular access care. This paternalistic approach has been shaped by directions from long-held clinical practice guidelines and is reinforced by financial payment models linked with the prevalence of arteriovenous fistula in patients on hemodialysis. Awareness is growing that what may have initially seemed a medically and surgically appropriate approach might not always be focused on each individual's goals of care. Clinician's recommendations for vascular access often do not sufficiently consider the uncertainty surrounding the potential benefits of the decision or the cumulative impact of the decision on patient's quality of life. In the evolving health care landscape, it is time for the practice of hemodialysis vascular access to shift from a hierarchical doctor-patient approach to patient-centered care. In this article we review the current state of vascular access practice, present arguments why SDM is necessary in vascular access planning, review barriers and potential solutions to SDM implementation, and discuss future research contingent on an effective system of physician-patient participative decision-making in hemodialysis vascular access practice., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Vascular access planning is critical in the management of patients with advanced kidney disease who elect for hemodialysis for RRT. Policies put in place more than two decades ago attempted to standardize vascular access care around the model of optimal, namely arteriovenous fistula, and least preferred, namely central venous catheter, type of access. This homogenized approach to vascular access care emerged ineffective in the increasingly heterogeneous and complex dialysis population. The most recent vascular access guidelines acknowledge the limitations of standardized care and encourage tailoring vascular access care on the basis of patient and disease characteristics. In this article, we discuss available literature in support of patient-tailored access care on the basis of differences in vascular access outcomes by biologic and social factors-age, sex, and race. Further, we draw attention to the overlooked dimension of patient-reported preferences and shared decision making in the practice of vascular access planning. We discuss milestones to overcome as requisite steps to implement effective shared decision making in vascular access care. Finally, we take into consideration local practice cofactors as major players in vascular access fate. We conclude that a personalized approach to hemodialysis vascular access will require dynamic care specifically relevant to the individual on the basis of biologic factors, fluctuating clinical needs, values, and preferences., Competing Interests: M. Murea reports receiving research funding from Vifor Inc.; and reports being a scientific advisor or member as Subject Editor, BMC Nephrology and Nephrology (Carlton). K. Woo reports being a scientific advisor or member of Laminate Data Safety Monitoring Board, and the Journal of Vascular Surgery Editorial Board., (Copyright © 2021 by the American Society of Nephrology.)

Introduction: The optimal haemodialysis (HD) prescription-frequency and dose-for patients with incident dialysis-dependent kidney disease (DDKD) and substantial residual kidney function (RKF)-that is, renal urea clearance ≥2 mL/min/1.73 m 2 and urine volume ≥500 mL/day-is not known. The aim of the present study is to test the feasibility and safety of a simple, reliable prescription of incremental HD in patients with incident DDKD and RKF., Methods and Analysis: This parallel-group, open-label randomised pilot trial will enrol 50 patients from 14 outpatient dialysis units. Participants will be randomised (1:1) to receive twice-weekly HD with adjuvant pharmacological therapy for 6 weeks followed by thrice-weekly HD (incremental HD group) or outright thrice-weekly HD (standard HD group). Age ≥18 years, chronic kidney disease progressing to DDKD and urine output ≥500 mL/day are key inclusion criteria; patients with left ventricular ejection fraction <30% and acute kidney injury requiring dialysis will be excluded. Adjuvant pharmacological therapy (ie, effective diuretic regimen, patiromer and sodium bicarbonate) will complement twice-weekly HD. The primary feasibility end points are recruitment rate, adherence to the assigned HD regimen, adherence to serial timed urine collections and treatment contamination. Incidence rate of clinically significant volume overload and metabolic imbalances in the first 3 months after randomisation will be used to assess intervention safety., Ethics and Dissemination: The study has been reviewed and approved by the Institutional Review Board of Wake Forest School of Medicine in North Carolina, USA. Patient recruitment began on 14 June 2019, was paused between 13 March 2020 and 31 May 2020 due to COVID-19 pandemic, resumed on 01 June 2020 and will last until the required sample size has been attained. Participants will be followed in usual care fashion for a minimum of 6 months from last individual enrolled. All regulations and measures of ethics and confidentiality are handled in accordance with the Declaration of Helsinki., Trial Registration Number: NCT03740048; Pre-results., Competing Interests: Competing interests: The principal investigator (MM) received funding for this trial from Relypsa, Vifor Pharma. KK-Z has received commercial honoraria and/or support from Abbott, AbbVie, Alexion, AMAG Pharma, Amgen, AstraZeneca, Aveo, Baxter, Chugai, DaVita, Dr Schaer, Fresenius, Genentech, Haymarket Media, Hospira, Kabi, Keryx, National Institutes of Health, Novartis, PCORI, Pfizer, Relypsa, Resverlogix, Sandoz, Sanofi, Shire, UpToDate, Vifor and ZS Pharma., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Patients on extracorporeal membrane oxygenator (ECMO) therapy are critically ill and often develop acute kidney injury (AKI) during hospitalisation. Little is known about the association of exposure to and the effect of the type of ECMO and extent of renal recovery after AKI development., Aim of the Study: In patients who developed AKI, renal recovery was characterised as complete, partial or dialysis-dependent at the time of hospital discharge in both the Veno-Arterial (VA) and Veno-Venous (VV) ECMO treatment groups., Material and Methods: The study consisted of a single-centre retrospective cohort that includes all adult patients (n=125) who received ECMO treatment at a tertiary academic medical centre between 2015 to 2019. Data on demographics, type of ECMO circuit, comorbidities, exposure to nephrotoxic factors and receipt of renal replacement therapy (RRT) were collected as a part of the analysis. Acute Kidney Injury Network (AKIN) criteria were used for the diagnosis and classification of AKI. Group differences were assessed using Fisher's exact tests for categorical data and independent t-tests for continuous outcomes., Results: Sixty-four patients received VA ECMO, and 58 received VV ECMO. AKI developed in 58(91%) in the VA ECMO group and 51 (88%) in the VV ECMO group (p=0.77). RRT was prescribed in significantly higher numbers in the VV group 38 (75%) compared to the VA group 27 (47%) (p=0.0035). At the time of discharge, AKI recovery rate in the VA group consisted of 15 (26%) complete recovery and 5 (9%) partial recovery; 1 (2%) remained dialysis-dependent. In the VV group, 22 (43%) had complete recovery (p=0.07), 3(6%) had partial recovery (p=0.72), and 1 (2%) was dialysis-dependent (p>0.99). In-hospital mortality was 64% in the VA group and 49% in the VV group (p=0.13)., Conclusions: Renal outcomes in critically ill patients who develop AKI are not associated with the type of ECMO used. This serves as preliminary data for future studies in the area., Competing Interests: Conflict of interest None to declare., (© 2021 Braghadheeswar Thyagarajan, Mariana Murea, Deanna N. Jones, Amit K. Saha, Gregory B. Russell, Ashish K. Khanna, published by Sciendo.)

Background: Patients with end-stage renal disease (ESRD) have a high burden of physical and psychological symptoms. Many remain unrecognized for long periods of time, particularly in older adults. The best strategy to monitor patient-reported outcome measures (PROMs) has not been identified., Objective: To assess the feasibility of implementing an iPad-based symptom assessment tool in older adults with ESRD on hemodialysis (HD)., Methods: We designed an iPad application-delivery system for collecting electronic PROMs (ePROMs). Patient's ≥60 years of age with ESRD on HD were recruited from a single outpatient dialysis unit. Feasibility was evaluated based on recruitment, retention, and the system usability score (SUS). Assessments were completed at baseline, 3 months, and 6 months after enrollment. ANOVA was used to assess longitudinal symptom variability., Results: Twenty-two patients (49% recruitment rate) were enrolled, with an 82% retention at 6 months. Mean age was 69.4 years (SD 6.6), 63.6% were female, and 81.8% were African American. Participants reported minimal difficulty in using the app, with an overall SUS score of 77.6. There were no significant relationships between demographic characteristics (age, race, or education) and SUS. Baseline SF-12 physical score and SF-12 mental score were 40.4 (SD 9.1) and 33.9 (SD 6.7), respectively. No significant changes were seen in longitudinal ePROMs of pain, depression, or anxiety; but was seen in the dialysis symptom index., Conclusion: In older patients with ESRD, collection of iPad-based ePROMs is feasible. This process can overcome inefficiencies associated with paper questionnaires and enable systematic monitoring of symptom burden.

Systemic anticoagulation in maintenance hemodialysis (HD) has historically been considered necessary to maintain the extracorporeal circuit (ECC) and preserve dialysis efficiency. Unfractionated heparin (UFH) is the most commonly used anticoagulant due to low cost and staff familiarity. Despite widespread use, there is little standardization of heparin dosing protocols in the United States. Although the complication rates with UFH are low for the general population, certain contraindications have led to exploration in alternative anticoagulants in patients with end-stage kidney disease (ESKD). Here we review the current evidence regarding heparin dosing protocols, complications associated with heparin use, and discuss alternatives to UFH including anticoagulant-free routine HD., (© 2020 Wiley Periodicals LLC.)

Background: It is unclear whether surgical placement of an arteriovenous (AV) fistula (AVF) confers substantial clinical benefits over an AV graft (AVG) in older adults with end-stage kidney disease (ESKD). We report vascular access outcomes of a pilot clinical trial., Study Design: Pilot randomized parallel-group open-label trial., Setting & Participants: Patients 65 years and older with ESKD and no prior AV access receiving maintenance hemodialysis through a tunneled central venous catheter referred for AV access placement by their treating nephrologist., Intervention: Participants were randomly assigned in a 1:1 ratio to surgical placement of an AVG or AVF., Outcomes: Index AV access primary failure, successful cannulation, adjuvant interventions and infections., Results: Of 122 older adults receiving hemodialysis and no prior AV access surgery, 24% died before (n = 18) or were too sick for (n = 11) referral for a permanent AV access. Of 46 eligible patients, 36 (78%) consented and were randomly assigned to AVG (n = 18) and AVF (n = 18) placement, of whom 13 (72%) and 16 (89%) underwent index AV access surgical placement, respectively. At a median follow-up of 321.0 days, primary AV access failure was noted in 31% in each group. The proportion of patients with successful cannulation was 62% (8 of 13) in the AVG and 50% (8 of 16) in the AVF group; median times to successful cannulation were 75.0 and 113.5 days, respectively. Endovascular procedures were recorded in 38% and 44%, and surgical reinterventions, in 23% and 25%, respectively. AV access infection was seen in 3 (23%) and 2 (13%) patients, respectively., Limitations: Small sample size precludes statistical inference., Conclusions: Almost one-quarter of older adults with incident ESKD and a central venous catheter as primary access were not referred for AV access placement due to medical reasons. Based on these limited results, there is little reason to favor either an AVF or AVG in this population until results from a larger randomized clinical trial become available., Funding: Government funding to an author (Dr Murea is supported by National Institutes of Health∖National Institute on Aging grant 1R03 AG060178-01)., Trial Registration: NCT03545113., (© 2021 The Authors.)

Purpose of Review: Conventional standardization of haemodialysis for treatment of end-stage kidney disease (ESKD) is predicated upon the fixed construct of one disease stage and one patient category. Increasingly recognized are subgroups of patients for whom less-intensive haemodialysis, such as incremental or decremental haemodialysis, could be employed., Recent Findings: Almost 30% of patients with incident ESKD have clinical and residual kidney function (RFK) parameters that could accommodate less-intensive haemodialysis. In one study, patients with incident ESKD and substantial RKF treated with low-dose haemodialysis had similar mortality rate as those treated with standard-dose haemodialysis, adding to the evidence that endogenous kidney function -- when present -- can complement less-intensive haemodialysis schedules. Hazards related to incremental haemodialysis include insidious development of fluid overload and higher rates of fluid removal. Finally, deintensification of haemodialysis treatment could be employed in patients with ESKD who seek conservative care., Summary: A shift in approach to ESKD from a dichotomous frame -- disease presence versus absence -- to stages of dialysis-dependent kidney disease, each stage associated with attuned haemodialysis intensity, has been proposed. Haemodialysis standardization and personalization -- often considered mutually exclusive -- can be combined in incremental haemodialysis. Data from ongoing and future randomized clinical trials, comparing less-intensive with standard haemodialysis schedules, are required to change practice.

Background: Kidney risk variants (KRVs) in the APOL1 gene are associated with mitochondrial dysfunction. However, the molecular spectrum of metabolites affected by the G1 and G2 KRVs, and the downstream mitochondrial pathways they affect, remain unknown., Methods: We performed a metabolomics analysis using HEK293 Tet-on cells conditionally expressing APOL1 G0, G1, and G2 KRVs to determine the patterns of metabolites and pathways potentially involved in nephropathy. The Welch two-sample t test, matched-pairs t test, and two-way repeated measures ANOVA were used to identify differential metabolites. Random forest, a supervised classification algorithm that uses an ensemble of decision trees, and the mean-decrease-accuracy metric were applied to prioritize top metabolites., Results: Alterations in the tricarboxylic acid cycle, increased fatty acid oxidation, and compromised redox homeostasis were the major pathways affected by overexpression of APOL1 KRVs., Conclusions: Impairment of mitochondrial membrane respiratory chain complex I appeared to account for critical metabolic consequences of APOL1 KRVs. This finding supports depletion of the mitochondrial membrane potential, as has been reported., Competing Interests: Wake Forest University Health Sciences and B. Freedman have rights to an issued US patent related to APOL1 genetic testing. B. Freedman is a consultant for AstraZeneca Pharmaceuticals and RenalytixAI. All remaining authors have nothing to disclose., (Copyright © 2020 by the American Society of Nephrology.)

Background: Although older adults encompass almost half of patients with advanced chronic kidney disease, it remains unclear which long-term hemodialysis vascular access type, arteriovenous fistula or arteriovenous graft, is optimal with respect to effectiveness and patient satisfaction. Clinical outcomes based on the initial AV access type have not been evaluated in randomized controlled trials. This pilot study tested the feasibility of randomizing older adults with advanced kidney disease to initial arteriovenous fistula versus graft vascular access surgery., Methods: Patients 65 years or older with pre-dialysis chronic kidney disease or incident end-stage kidney disease and no prior arteriovenous vascular access intervention were randomized in a 1:1 ratio to undergo surgical placement of a fistula or a graft after providing informed consent. Trial feasibility was evaluated as (i) recruitment of ≥ 70% of eligible participants, (ii) ≥ 50 to 70% of participants undergo placement of index arteriovenous access within 90 to 180 days of enrollment, respectively, (iii) ≥ 80% adherence to study-related assessments, and (iv) ≥ 70% of participants who underwent index arteriovenous access placement will have a follow-up duration of ≥ 12 months after index surgery date., Results: Between September 2018 and October 2019, 81% (44/54) of eligible participants consented and were enrolled in the study; 11 had pre-dialysis chronic kidney disease, and 33 had incident or prevalent end-stage kidney disease. After randomization, 100% (21/21) assigned to arteriovenous fistula surgery and 78% (18/23) assigned to arteriovenous graft surgery underwent index arteriovenous access placement within a median (1st, 3rd quartile) of 5.0 (1.0, 14.0) days and 13.0 (5.0, 44.3) days, respectively, after referral to vascular surgery. The completion rates for study-specific assessments ranged between 40.0 and 88.6%. At median follow-up of 215.0 days, 5 participants expired, 7 completed 12 months of follow-up, and 29 are actively being followed. Assessments of grip strength, functional independence, and vascular access satisfaction were completed by > 85% of patients who reached pre-specified post-operative assessment time point., Conclusions: Results from this study reveal it is feasible to enroll and randomize older adults with advanced kidney disease to one of two different arteriovenous vascular access placement surgeries. The study can progress with minor protocol adjustments to a multisite clinical trial., Trial Registration: Clinical Trials ID, NCT03545113., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Introduction: APOL1 G1 and G2 nephropathy-risk variants cause mitochondrial dysfunction and contribute to kidney disease. Analyses were performed to determine the genetic regulation of APOL1 and elucidate potential mechanisms in APOL1 -nephropathy., Methods: A global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed., Results: APOL1 genotypes did not alter APOL1 expression levels in the global gene expression analysis. Expression quantitative trait locus (eQTL) analysis in polyinosinic-polycytidylic acid (poly IC)-stimulated renal tubule cells revealed that single nucleotide polymorphism (SNP) rs513349 adjacent to BAK1 was a trans eQTL for APOL1 and a cis eQTL for BAK1 ; APOL1 and BAK1 were co-expressed in cells. BAK1 knockout in a human podocyte cell line resulted in diminished APOL1 protein, supporting a pivotal effect for BAK1 on APOL1 expression. Because BAK1 is involved in mitochondrial dynamics, mitochondrial morphology was examined in primary renal tubule cells and HEK293 Tet-on cells of various APOL1 genotypes. Mitochondria in APOL1 wild-type (G0G0) tubule cells maintained elongated morphology when stimulated by low-dose poly IC, whereas those with G1G1, G2G2, and G1G2 genotypes appeared to fragment. HEK293 Tet-on cells overexpressing APOL1 G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2., Conclusion: Results suggest the mitochondrial fusion/fission pathway may be a therapeutic target in APOL1 -nephropathy., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Pauci-immune necrotizing and crescentic glomerulonephritis (GN) is the most common etiology of rapidly progressive GN. Clinical presentation in those afflicted is usually related to rapid loss of kidney function. We report the case of a 70-year-old woman who came to medical attention for signs and symptoms related to lower-extremity deep vein thrombosis (DVT). At presentation, the patient had biochemical abnormalities consistent with active GN, which quickly progressed to rapid loss in kidney function requiring renal replacement therapy. Kidney biopsy revealed small-vessel vasculitis with glomerular crescents. Serologic studies were negative for antineutrophil cytoplasmic antibody antibodies and other causes of acute GN. Plasmapheresis, immunosuppressive, and anticoagulant therapies were prescribed. Absence of other apparent end-organ involvement with vasculitis pointed toward renal-limited small-vessel vasculitis, yet presence of unprovoked DVT argues for systemic vascular inflammation. This case illustrates that venous thrombosis can be the presenting manifestation in patients with vasculitis and silent, severe end-organ involvement. The epidemiology and pathophysiology of venous thromboembolism in small-vessel vasculitis are discussed in this report., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background: Apolipoprotein L1 gene (APOL1) G1 and G2 kidney-risk variants (KRVs) cause CKD in African Americans, inducing mitochondrial dysfunction. Modifying factors are required, because a minority of individuals with APOL1 high-risk genotypes develop nephropathy. Given that APOL1 function is pH-sensitive and the pH of the kidney interstitium is <7, we hypothesized the acidic kidney interstitium may facilitate APOL1 KRV-induced mitochondrial dysfunction., Methods: Human embryonic kidney (HEK293) cells conditionally expressing empty vector (EV), APOL1-reference G0, and G1 or G2 KRVs were incubated in media pH 6.8 or 7.4 for 4, 6, or 8 h. Genotype-specific pH effects on mitochondrial length (µm) were assessed using confocal microscopy in live cells and Fiji derivative of ImageJ software with MiNA plug-in. Lower mitochondrial length indicated fragmentation and early dysfunction., Results: After 6 h doxycycline (Dox) induction in pH 6.8 media, G2-expressing cells had shorter mitochondria (6.54 ± 0.40) than cells expressing EV (7.65 ± 0.72, p = 0.02) or G0 (7.46 ± 0.31, p = 0.003). After 8 h Dox induction in pH 6.8 media, both G1- (6.21 ± 0.26) and G2-expressing cells had shorter mitochondria (6.46 ± 0.34) than cells expressing EV (7.13 ± 0.32, p = 0.002 and p = 0.008, respectively) or G0 (7.22 ± 0.45, p = 0.003 and p = 0.01, respectively). Mitochondrial length in cells incubated in pH 7.4 media were comparable after 8 h Dox induction regardless of genotype. APOL1 mRNA expression and cell viability were comparable regardless of pH or genotype after 8 h Dox induction., Conclusion: Acidic pH facilitates early mitochondrial dysfunction induced by APOL1 G1 and G2 KRVs in HEK293 cells. We propose that the acidic kidney interstitium may play a role in APOL1-mediated mitochondrial pathophysiology and nephropathy., (© 2020 S. Karger AG, Basel.)

The prescription of hemodialysis (HD) in patients with incident end-stage kidney disease (ESKD) is fundamentally empirical. The abrupt transition from nondialysis chronic kidney disease (CKD) to thrice-weekly in-center HD of much the same dialysis intensity as in those with prevalent ESKD underappreciates the progressive nature of kidney disease whereby the decline in renal function has been gradual and ongoing-including at the time of HD initiation. Adjuvant pharmacologic treatment (i.e., diuretics, acid buffers, potassium binders), coupled with residual kidney function (RKF), can complement an initial HD regimen of lower intensity. Barriers to less intensive HD in incident ESKD include risk of inadequate clearance of uremic toxins due to variable and unexpected loss of RKF, lack of patient adherence to assessments of RKF or adjustment of HD intensity, increased burden for all stakeholders in the dialysis units, and negative financial repercussions. A stepped dialysis regimen with scheduled transition from time-delineated twice-weekly HD to thrice-weekly HD could represent an effective and safe strategy to standardize incremental HD in patients with CKD transitioning to early-stage ESKD. Patients' adherence and survival as well as other clinical outcomes should be rigorously evaluated in clinical trials before large-scale implementation of different incremental schedules of HD. This review discusses potential benefits of and barriers to alternative dialysis regimens in patients with incident ESKD, with emphasis on twice-weekly HD with pharmacologic therapy, and summarizes in-progress clinical trials of incremental HD schedules., (© 2019 International Society of Nephrology. Published by Elsevier Inc.)

Vascular access for hemodialysis has a long and rich history. This article highlights major innovations and milestones in the history of angioaccess for hemodialysis. Advances in achievement of lasting hemodialysis access, swift access transition, immediate and sustaining access to vascular space built the momentum at different turning points of access history and shaped the current practice of vascular access strategy. In the present era, absent of large-scale clinical trials to validate practice, the ever-changing demographic and comorbidity makeup of the dialysis population pushes against stereotypical angioaccess goals. The future of hemodialysis vascular access would benefit from proper randomized clinical trials and acclimatization to clinical contexts., (© 2019 Wiley Periodicals, Inc.)

Background: Incremental hemodialysis (HD) is seldom prescribed in the United States. This study describes longitudinal changes in volume management in patients with incident end-stage kidney disease (ESKD) initiated on bi-weekly (twice a week) HD, later converted to thrice-weekly HD., Materials and Methods: 23 patients (mean age 65.6 years, 48% male, and 30% black) were included. Repeated measurement analysis of regression was used to test for differences in interdialytic weight gain (IDWG) and ultrafiltration rate (UFR) over three dialysis periods: the first 3 months of bi-weekly HD, the last 3 months of bi-weekly HD, and the first 3 months of thrice-weekly HD., Results: The mean transition time to thrice-weekly HD was 332.9 days. Compared to the first 3 months of HD, the IDWG and UFR increased by 0.6 kg and 2.2 mL/kg/h in the last 3 months of bi-weekly HD (p = 0.02 and 0.009, respectively) and by 0.7 kg and 2.1 mL/kg/h in the first 3 months of thrice-weekly HD (p = 0.002). The average proportion of patients with IDWG > 5.7% of the dry weight was 0% in the first 3 months of bi-weekly HD, 12% in the last 3 months of bi-weekly HD, and 4% in the first 3 months of thrice-weekly HD; while the average proportion of patients with UFR > 10 mL/kg/h was 16%, 39%, and 25%, respectively., Conclusion: Fluid management in incident-ESKD patients receiving bi-weekly HD deteriorates prior to conversion to thrice-weekly HD. Further studies are needed to optimize the prescription of incremental HD.

Timely placement of an arteriovenous (AV) vascular access (native AV fistula [AVF] or prosthetic AV graft [AVG]) is necessary to limit the use of tunneled central venous catheters (TCVC) in patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD). National guidelines recommend placement of AVF as the AV access of first choice in all patients to improve patient survival. The benefits of AVF over AVG are less certain in the older adults, as age-related biological changes independently modulate patient outcomes. This manuscript describes the rationale, study design and protocol for a randomized controlled pilot study of the feasibility and effects of AVG-first access placement in older adults with no prior AV access surgery. Fifty patients age ≥65 years, with incident ESKD on HD via TCVC or advanced kidney disease facing imminent HD initiation, and suitable upper extremity vasculature for initial placement of an AVF or AVG, will be randomly assigned to receive either an upper extremity AVG-first (intervention) or AVF-first (comparator) access. The study will establish feasibility of randomizing older adults to the two types of AV access surgery, evaluate relationships between measurements of preoperative physical function and vascular access development, compare vascular access outcomes between groups, and gather longitudinal assessments of upper extremity muscle strength, gait speed, performance of activities of daily living, and patient satisfaction with their vascular access and quality of life. Results will assist with the planning of a larger, multicenter trial assessing patient-centered outcomes.

Uric acid-mediated biological effects are milieu dependent. In a physiological milieu, serum uric acid serves as an antioxidant; when homeostasis is perturbed, divergent effects are observed depending on the clinical context. Several epidemiologic studies indicated the presence of a direct relationship between higher concentrations of serum uric acid and cardiovascular mortality; yet not all studies support this conclusion. Although high serum levels of uric acid are associated with higher mortality in patients with nondialysis-dependent chronic kidney disease and perhaps in those with end-stage kidney disease receiving peritoneal dialysis, the opposite relationship is seen in patients with end-stage kidney disease on hemodialysis. This review discusses the pathologic mechanisms associated with elevated serum uric acid levels by clinical context; examines the interplay between uric acid metabolism and modality of renal replacement therapy; and presents hypotheses to rationalize the disparate associations between incremental levels of serum uric acid and survival across the continuum of kidney disease and by type of renal replacement therapy., (© 2018 Wiley Periodicals, Inc.)

Background: Appendicular skeletal muscle mass index and muscle attenuation (density) are negatively associated with mortality in European-derived populations., Objectives: The present analyses assessed association between axial skeletal muscle density and muscle index with mortality in European Americans with type 2 diabetes mellitus (T2D)., Design: Single-center observational study., Setting: Diabetes Heart Study., Participants: 839 European Americans with T2D., Methods: Computed tomography-measured psoas and paraspinous muscle mass index (cross sectional area/height2) and radiographic density (Hounsfield Units) were assessed in all participants. A Cox proportional hazards model was computed. The fully-adjusted model included covariates age, sex, body mass index, smoking, alcohol use, diabetes duration, insulin use, hormone replacement therapy (women), prevalent cardiovascular disease (CVD), hypertension, and coronary artery calcified atherosclerotic plaque mass score. Deaths were recorded in the National Death Index data through December 31, 2015., Results: Participants included 428 women and 411 men with median (25th, 75th quartile) age 62.8 (56.1, 69.1) years and diabetes duration 8.0 (5.0, 14.0) years. After 11.9 (9.4, 13.3) years of follow-up, 314 (37.4%) of participants were deceased. In the fully-adjusted model, psoas muscle density (hazard ratio [HR] 0.81, p<0.001), psoas muscle index (HR 0.82, p=0.008), and paraspinous muscle density (HR 0.85, p=0.003) were inversely associated with mortality. Paraspinous muscle index was not significantly associated with mortality (HR 0.90, p=0.08). Results did not differ significantly between men and women., Conclusions: In addition to established risk factors for mortality and CVD, higher psoas muscle index, psoas muscle density, and paraspinous muscle density were significantly associated with lower all-cause mortality in European Americans with T2D., Competing Interests: No conflicts exist

Background: Viral infections can trigger chronic kidney disease (CKD) and the urine virome may inform risk. The Natural History of APOL1-Associated Nephropathy Study (NHAANS) reported that urine JC polyomavirus (JCPyV) associated with a lower risk of APOL1-associated nephropathy in African Americans. Herein, association was assessed between urine JCPyV with CKD in African Americans independent from the APOL1 genotype., Methods: Quantitative polymerase chain reaction was performed for urinary detection of JCPyV and BK polyoma virus (BKPyV) in 200 newly recruited nondiabetic African Americans. A combined analysis was performed in these individuals plus 300 NHAANS participants., Results: In the 200 new participants, urine JCPyV was present in 8.8% of CKD cases and 45.8% of nonnephropathy controls (P = 3.0 × 10-8). In those with APOL1 renal-risk genotypes, JCPyV was detected in 5.1% of cases and 40.0% of controls (P = 0.0002). In those lacking APOL1 renal-risk genotypes, JCPyV was detected in 12.2% of cases and 48.8% of controls (P = 8.5 × 10-5). BKPyV was detected in 1.3% of cases and 0.8% of controls (P  =  0.77). In a combined analysis with 300 NHAANS participants (n = 500), individuals with urine JCPyV had a 63% lower risk of CKD compared with those without urine JCPyV (odds ratio 0.37; P = 4.6 × 10-6). RNA fluorescence in situ hybridization confirmed the presence of JCPyV genomic DNA and JCPyV messenger RNA (mRNA) in nondiseased kidney., Conclusions: Inverse relationships exist between JCPyV viruria and non-diabetic CKD. Future studies should determine whether renal inflammation associated with CKD is less permissive for JCPyV reactivation/replication or whether JCPyV is a marker of reduced host immune responsiveness that diminishes immune pathologic contributions to CKD.

Introduction: Mitochondrial dysfunction plays an important role in the pathophysiology of kidney disease. Inhibitors of mitochondrial metabolism are being developed for the treatment of solid organ and hematologic malignancies. We describe the incidence and clinical features of acute kidney injury (AKI) in patients treated with the antimitochondrial drug CPI-613., Methods: We identified 33 patients with relapsed or refractory malignancy, previously enrolled in 3 open-label phase II studies, who received single-agent CPI-613 chemotherapy. AKI was defined by the Kidney Disease Improving Global Outcomes serum creatinine criteria. Participants were followed for a median (25th-75th percentile) of 120.0 (74.0-301.0) days. Risk factors for AKI were assessed by proportional hazards regression using univariate and multivariate analyses., Results: Participants had baseline mean (SD) age of 63.8 (11.6) years and serum creatinine 0.9 (0.3) mg/dl. AKI developed in 9 (27%) patients; chart review failed to identify a potential cause of AKI other than CPI-613 administration in 5 (15%) patients, of whom 1 had AKI stage 1, 1 had AKI stage 2, and 3 experienced AKI stage 3. Time from initiation of CPI-613 treatment to AKI was 51.0 (16.0-58.0) days. Age, per 5-year increase, was associated with higher risk of AKI (adjusted hazard ratio 2.01, 95% confidence interval 1.06-3.79, P  = 0.03). Follow-up serum creatinine was available in 4 participants 174.8 (139.6) days after the episode of AKI; 3 patients had complete recovery in kidney function and 1 had partial recovery., Conclusion: AKI is a possible complication during treatment with mitochondria-targeted chemotherapy.

Aim: Recent studies revealed a correlation between skeletal muscle mass index and density with longevity; these studies largely evaluated appendicular skeletal muscles in older Caucasians. This retrospective cohort study assessed the association between axial skeletal muscles size and density with survival in African Americans with type 2 diabetes mellitus., Methods: Psoas and paraspinous muscle mass index (cross sectional area/height 2 ) and radiographic density (in Hounsfield Units) were measured using computed tomography in African American-Diabetes Heart Study participants, 314 women and 256 men, with median (25th, 75th quartile) age 55.0(48.0, 62.0) and 57.0(50.0, 64.0) years, respectively. Covariates in fully-adjusted model included age, sex, BMI, smoking, hormone replacement therapy (women), cardiovascular disease, hypertension, coronary artery calcified plaque mass, carotid artery calcified plaque mass, and African ancestry proportion., Results: After median of 7.1(5.9, 8.2) years follow-up, 30(9.6%) of women and 49(19.1%) of men were deceased. In fully-adjusted models, psoas muscle mass index and paraspinous muscle mass index were inversely associated with mortality in men (psoas muscle mass index, hazard ratio [HR] = 0.61, P = 0.004; paraspinous muscle mass index, HR = 0.64, P = 0.004), but not in women. Psoas and paraspinous muscle densities did not associate with all-cause mortality. A penalized Cox regression that involved all covariates and predictors associated with mortality showed that only paraspinous muscle mass index remained a significant predictor of mortality (HR = 0.65, P = 0.02)., Conclusion: Independent from established risk factors for mortality, higher psoas and paraspinous muscle index associate with reduced all-cause mortality in middle-aged African American men with type 2 diabetes mellitus., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Cisplatin remains the pivotal chemotherapy in squamous cell carcinoma of the head and neck (SCCHN), with nephrotoxicity considered the dose-limiting toxicity. The purpose of our study was to propose an outpatient high-dose cisplatin protocol aimed at preventing nephrotoxicity and to analyze the results of its utilization in patients with SCCHN treated with concurrent radiotherapy., Materials and Methods: We retrospectively evaluated 82 SCCHN patients treated with outpatient high-dose cisplatin concurrent with radiotherapy at our institution. Acute kidney injury (AKI) and chronic kidney disease were defined by Kidney Disease Improving Global Outcomes criteria. Associated factors were identified using analysis of covariance models for categorical variables and adjusted Pearson correlations for continuous variables., Results: The incidence of AKI during treatment was 34.2%. With a median follow-up of 25.7 months, the average decrease in estimated glomerular filtration rate was 12.57 mL/min/1.73 m (SD=18.58). At 1 year and at last follow-up, 5.4% and 4.4% of patients had estimated glomerular filtration rate <60 mL/min/1.73 m. Predictors associated with AKI and chronic kidney disease were: lower baseline weight and creatinine, higher baseline creatinine clearance, smoking, female sex, African American race, hypertension, and increased hydration and magnesium replacement requirements., Conclusions: We encountered limited early and late nephrotoxicity. Importantly, nephrotoxicity was not the main dose-limiting toxicity. Our results emphasize the importance of close monitoring and additional replacement of water and electrolytes as needed. A consistent method of measuring and reporting chemotherapy-induced nephrotoxicity would be a valuable contribution to the literature.

Introduction: The dose of unfractionated heparin (UFH) administered during hemodialysis (HD) varies widely. This prospective study evaluated the safety and efficacy of UFH dose de-escalation., Methods: Sixty-six prevalent patients on HD receiving UFH per standard-dose protocol (load dose [LD] 50-75 units/kg, maintenance dose [MD] 500-1000 units/hour) had heparin prescription converted to low-dose protocol (start LD 15 units/kg and MD 500 units/hour; dose adjusted in small increments based on assessments of extracorporeal blood circuit). Coagulation parameters, dialysis adequacy, dialyzer clotting, anemia management, and dialyzer reuse rates were compared based on the heparin protocol., Findings: Mean(SD) UFH dose per HD session, before and after protocol conversion, was 6178(2644) and 2913(1116) units, respectively (P < 0.0001). This corresponded to LD 52.1(16.6) units/kg and MD 615(207) units/hour with standard-dose protocol, and LD 18.3(6.5) units/kg and MD 505(27) units/hour with low-dose protocol (P < 0.0001). Mid and postdialysis aPTT was 55.3(31.2) and 35.1(7.8) seconds before, and 37.3(12.9) and 31.5(5.3) seconds after conversion (P = 0.007 and 0.003, respectively); no significant changes in D-dimer levels occurred. Low-dose UFH was associated with a small increase in URR and spKt/V (73.0 and 1.54) compared with dialysis clearance on standard-dose UFH (71.2 and 1.48, respectively, P = 0.02). Weekly dose of ESA decreased by 2388 units postconversion (P = 0.03), while hemoglobin levels and the weekly dose of intravenous iron did not change (P = 0.16 and 0.78). A small rise in the rate of moderate dialyzer clotting at the end of HD was noted with low-dose UFH (5.7% vs. 7.5%, P = 0.002); the rate of severe dialyzer clotting events did not change (P = 0.91). No change in the dialyzer reuse rate was noted (18.5 vs. 17.0 treatments, P = 0.26)., Discussion: Low-dose heparinization did not compromise dialysis adequacy and permitted ESA dose reduction. Our findings suggest that in prevalent patients on HD, UFH dose of 15-20 units/kg loading and 500 units/hour maintenance was medically safe and effective., (© 2017 International Society for Hemodialysis.)

APOL1 G1 and G2 variants facilitate kidney disease in blacks. To elucidate the pathways whereby these variants contribute to disease pathogenesis, we established HEK293 cell lines stably expressing doxycycline-inducible (Tet-on) reference APOL1 G0 or the G1 and G2 renal-risk variants, and used Illumina human HT-12 v4 arrays and Affymetrix HTA 2.0 arrays to generate global gene expression data with doxycycline induction. Significantly altered pathways identified through bioinformatics analyses involved mitochondrial function; results from immunoblotting, immunofluorescence, and functional assays validated these findings. Overexpression of APOL1 by doxycycline induction in HEK293 Tet-on G1 and G2 cells led to impaired mitochondrial function, with markedly reduced maximum respiration rate, reserve respiration capacity, and mitochondrial membrane potential. Impaired mitochondrial function occurred before intracellular potassium depletion or reduced cell viability occurred. Analysis of global gene expression profiles in nondiseased primary proximal tubule cells from black patients revealed that the nicotinate phosphoribosyltransferase gene, responsible for NAD biosynthesis, was among the top downregulated transcripts in cells with two APOL1 renal-risk variants compared with those without renal-risk variants; nicotinate phosphoribosyltransferase also displayed gene expression patterns linked to mitochondrial dysfunction in HEK293 Tet-on APOL1 cell pathway analyses. These results suggest a pivotal role for mitochondrial dysfunction in APOL1 -associated kidney disease., (Copyright © 2017 by the American Society of Nephrology.)

Background: Arteriovenous accesses (AVA) in patients performing hemodialysis (HD) are labeled "permanent" for AV fistulas (AVF) or grafts (AVG) and "temporary" for tunneled central venous catheters (TCVC). Durability and outcomes of permanent vascular accesses based on the sequence in which they were placed or used receives little attention. This study analyzed longitudinal transitions between TCVC-based and AVA-based HD outcomes according to the order of placement., Methods: All 391 patients initiating chronic HD via a TCVC between 2012 and 2013 at 12 outpatient academic dialysis units were included in this study. Chronological distributions of HD vascular accesses were recorded over a mean (SD) of 2.8 (0.9) years and sequentially grouped into periods for TCVC-delivered and AVA-delivered (AVF or AVG) HD. Primary AVA failure and cumulative access survival were evaluated based on access placement sequence and type, adjusting for age., Results: In total, 92.3% (361/391) of patients underwent 497 AVA placement surgeries. Analyzing the initial 3 surgeries, primary AVF failure rates increased with each successive fistula placement (p = 0.008). Among the 82.9% (324/391) of TCVC patients successfully converted to an AVA, 30.9% returned to a TCVC, followed by a 58.0% conversion rate to another AVA. Annual per-patient vascular access transition rates were 2.02 (0.09) HD periods using a TCVC and 0.54 (0.03) HD periods using an AVA. Comparing the first AVA used with the second, cumulative access survivals were 701.0 (370.0) vs. 426.5 (275.0) days, respectively. Excluding those never converting to an AVF or AVG, 169 (52.2%) subsequently converted from a TCVC to a permanent access and received HD via AVA for ≥80% of treatments., Conclusions: HD vascular access outcomes differ based on the sequence of placement. In spite of frequent AVA placements, only half of patients effectively achieved a "permanent" vascular access and used an AVA for the majority of HD treatments., (© 2017 S. Karger AG, Basel.)