A single-centre, anonymous survey study was conducted to investigate patient experience and quality of life (Kidney Disease Quality of Life-36) in individuals receiving incremental haemodialysis, with all 20 eligible patients participating. Patients expressed high satisfaction with incremental haemodialysis and a strong preference over conventional haemodialysis regimens. Quality-of-life scores were consistent with broader dialysis populations, but overall satisfaction with care was high, supporting the potential for incremental haemodialysis expansion.

BackgroundIncremental peritoneal dialysis (PD) has been recommended as a patient-focused prescription; however, its safety and potential clinical benefits are based on retrospective studies.MethodsWe conducted a pilot, randomized controlled study comparing 5-day versus 7-day/week PD in incident patients with preserved residual kidney function in three centers in Australia. Modality of PD accorded to patient and clinician preferences for both groups. Participants on 5-day PD were transitioned to daily PD if symptoms of uremia did not respond to an increase in dialysate volume, or if residual renal creatinine clearance fell to <50 L/week/1.73m2. Duration of the 5-day regimen, quality of life, and clinical outcomes were compared to standard treatment over 12 months.ResultsTwenty-four participants were randomized to 7-day (n = 13) or 5-day (n = 11) PD. At baseline, age, gender, diabetes prevalence, and estimated glomerular filtration rate were similar. The mean and median durations of the 5-day prescription were 8.4 ± 4.7 and 12 (IQR 5-12) months, respectively. On average, participants in the 5-day Group had 73 dialysis-free days/person and utilized less PD fluid (957 ± 218 vs. 1558 ± 436 L/person, P < 0.0001). No differences were observed in peritonitis (0.12 vs. 0.26 episodes/patient-year) or hospitalization (0.12 vs. 0.09 episodes/patient-year) rates between 5- and 7-day groups, respectively. Although physical, mental, and kidney-disease composite scores were comparable between groups, sleep quality and patient satisfaction were higher in the 5-day Group.ConclusionIncremental PD was feasible in patients with preserved residual kidney function in the first year of dialysis and was not associated with more complications compared with daily PD. Differences observed in sleep quality of treatment satisfaction are hypothesis-generating and warrant further evaluation.

Disordered energy regulation within the kidney represents an important therapeutic target to reduce the severity of acute kidney injury and subsequent fibrosis. AMP-activated protein kinase (AMPK) is stimulated in situations of cellular energy deprivation to act as a key regulator of cellular and systemic energy metabolism. AMPK activation has been shown to be protective against renal injury and fibrosis in numerous experimental studies using metformin and aminoimidazole-4-carboxamide ribonucleotide. However, studies with these traditional AMPK activators are limited by these agents being indirect activators of AMPK, with unwanted off-target effects that may limit their use. Novel AMPK activators represent a promising new therapy in kidney protection, as well as in a range of other chronic diseases. AMPK phosphorylates multiple targets to regulate numerous pathways, thereby enabling multiple mechanisms to reduce kidney injury. This review outlines important mechanisms of renal injury and fibrosis as well as the current landscape of novel AMPK activators. It outlines experimental evidence for mechanisms of novel AMPK activators and how these relate to injury and fibrosis within the kidney. Finally, it discusses the potential of these agents, as well as current challenges in their development. SIGNIFICANCE STATEMENT: Multiple studies have identified dysregulated energy metabolism as a treatment target for kidney disease, revealing novel AMP-activated protein kinase (AMPK) activators as a promising new therapy to address this opportunity for protection against kidney injury and fibrosis. Despite this promise, novel AMPK activators are yet to find a clinical role for kidney disease or other conditions. Barriers to be considered in future studies include concerns about cardiac hypertrophy and oncogenesis as well as elucidation of precise pharmacokinetic properties. Nonetheless, the large volume of beneficial preclinical data for kidney health provides motivation for future studies to address these needs.

Introduction: Angiotensin II may reduce muscle ischemia during intermittent hemodialysis and thereby decrease the incidence and/or intensity of intradialytic muscle cramps. We aimed to test whether angiotensin II infusion during intermittent hemodialysis is safe, feasible, and effective in the attenuation of muscle cramps. Methods: We performed a pilot, single-blinded, randomized crossover trial of patients receiving intermittent hemodialysis who frequently experience intradialytic muscle cramps. Patients were randomly allocated to receive either intravenous angiotensin II or placebo for the duration of their first dialysis session of the week. They crossed over to the alternate arm each week for four weeks. The primary outcome was safety. Secondary outcomes included cramp-related symptoms, hemodynamic parameters, dialysis prescription alterations, and biomarkers. Results: We studied 24 sessions in 6 patients. Intradialytic hypertension (systolic blood pressure >180mmHg) occurred more often with angiotensin II than with placebo (33% vs 17% sessions, P=0.64). There were no other adverse events. Compared with placebo, muscle cramps were less frequent (33% vs. 92% sessions, P=0.009) and of lower intensity with angiotensin II (median Brief Pain Inventory score 1.4 vs. 5.3; P<0.001; maximal Brief Pain Inventory score 1.2 vs. 6.0; P<0.001). Fluid bolus administration for cramps was less common during angiotensin II infusion than placebo (0% vs. 42% sessions, P=0.037). Conclusion: Angiotensin II increased blood pressure and heart rate but not cardiac output or levels of troponin, creatine kinase or renin. In conclusion, angiotensin II infusion during intermittent hemodialysis appears safe and effective at reducing intradialytic muscle cramps. These observations justify further investigation in larger controlled studies.

INTRODUCTION:Chronic active antibody-mediated rejection (AMR) is the leading cause of death-censored kidney allograft loss, with no proven treatments. While intravenous immunoglobulin (IVIG) has been used in certain cases, its efficacy is unknown. METHODS:In this open-label multicenter randomized controlled trial (VIPAR), participants with biopsy-proven chronic active AMR, were assigned to six doses (1 g/kg/month) of IVIG or no-IVIG. The primary end point was the difference in slopes of the chronic allograft damage index (CADI) scores between groups, across four allograft biopsies (baseline, three, six and 12 months). Secondary outcomes, assessed at baseline, three, six and 12 months, included change in estimated glomerular filtration rate (eGFR), change in donor-specific anti-HLA antibodies (DSA), allograft and patient survival, and change in intra-graft mRNA expression. RESULTS:Fifteen participants were randomized to each arm. Their median age was 54.3 years, 22 were male and mean eGFR was 43.3 ml/min/1.73m2. Participants in the no-IVIg group experienced a significant increase in mean CADI (+0.28/month, 95% confidence interval 0.14 to 0.41), while the IVIG group did not (-0.004/month, -0.13 to 0.12). Over two years, eGFR significantly declined more rapidly in the no-IVIG group (-1.1 ml/min/month, -1.5 to -0.7 ml/min/month) than the IVIG group (-0.4 ml/min/month, -0.8 to 0.03 ml/min/month). Differences in patient and allograft survival were not evident by 12 months. Intra-graft expression of 59 genes (mostly B-cell related) reduced with IVIG relative to no-IVIG. CONCLUSIONS:IVIG therapy was associated with stabilization in allograft histology and eGFR in kidney transplant recipients with chronic active AMR. TRIAL REGISTRATION:Registered at https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347495 with study number ACTRN12612000252819.

BACKGROUND:We review the impact of a nephrology key performance indicator (KPI) program implemented over a ten-year period in Victoria, Australia. The program enabled transparent comparison of performance across nephrology units, however improvement against performance targets was not consistent and better understanding of KPIs is required to promote quality improvement. AIM:We aimed to review the impact of the Victorian nephrology KPI programme over a 10-year period. METHODS:The KPI programme involved six KPIs related to the continuum of care for kidney replacement therapy: pre-dialysis education, vascular access at first haemodialysis, home dialysis rates, peritonitis rates, pre-emptive kidney transplantation and rates of transplantation/waitlisting. Data were collected monthly from the 10 Victorian nephrology services using a purpose-designed website portal. Results were analysed and reported every 3 months. We present a summary of each KPI and discuss changes over the 10-year period. RESULTS:KPI data demonstrated significant differences in performance across KPIs after implementation, particularly in rates of home dialysis and transplant waitlisting. Changes within units were sometimes significant, but across Victoria, performance was relatively static. Over 10 years, there was a lack of significant improvement in clinical performance in several indicators and multiple changes to KPI targets were made. CONCLUSION:The KPI programme enabled comparison of performance across nephrology units, but improvement in performance targets was not consistent over the 10-year period and the programme served as a means for benchmarking perhaps, rather than a quality improvement tool. Better understanding of each KPI and resources available for quality improvement is crucial for the success of a KPI programme.

Acute kidney injury (AKI) involves necrotic damage to the renal tubular epithelium accompanied by inflammation and cell death-a pattern referred to as necroinflammation. Obesity, a global health crisis, stimulates chronic low-grade inflammation; however, its influence on AKI is not well understood. We examined folic acid-induced AKI (FA-AKI) in obese mice fed a high-fat diet (HFD) for 6 weeks, compared to mice on a control diet (CD). Following FA-AKI, obese HFD mice showed significantly higher serum urea and creatinine, more severe morphological injury, and greater expression of the injury marker NGAL. RT-PCR revealed that AKI with obesity increased inflammation, evidenced by increased Il6 and Ccl2 mRNA expression. Tubular vacuolation and Oil Red O staining revealed tubular cell lipid accumulation with HFD. Higher levels of receptor-interacting protein kinase-3 (RIPK3) mRNA and protein were seen in FA-AKI mice on the HFD, in association with significantly increased expression of phosphorylated mixed lineage kinase domain-like protein (pMLKL), the key trigger of necroptotic cell death, in tubular epithelium. While FA-AKI altered ferroptosis markers (e.g., Acsl4 ↓, Gpx4 ↑), these changes were unaffected by HFD. Apoptosis markers were increased by FA-AKI but unaffected by HFD, and similarly, markers of autophagic flux were altered by FA-AKI but not significantly changed by HFD. In summary, these data reveal worsened AKI and increased necroinflammation in obese mice, with increased activation of necroptosis. These descriptive findings add to current evidence for the importance of necroinflammation in AKI and suggest necroptosis may be a key obesity-sensitive process in renal injury, identifying these as potential therapeutic targets in obese AKI patients.

Acute kidney injury (AKI) disrupts energy metabolism. Targeting metabolism through AMP-activated protein kinase (AMPK) may alleviate AKI. ATX-304, a pan-AMPK activator, was evaluated in C57Bl/6 mice and tubular epithelial cell (TEC) cultures. Mice received ATX-304 (1 mg/g) or control chow for 7 days before cisplatin-induced AKI (CI-AKI). Primary cultures of tubular epithelial cells (TECs) were pre-treated with ATX-304 (20 µM, 4 h) prior to exposure to cisplatin (20 µM, 23 h). ATX-304 increased acetyl-CoA carboxylase phosphorylation, indicating AMPK activation. It protected against CI-AKI measured by serum creatinine (control 0.05 + 0.03 mM vs ATX-304 0.02 + 0.01 mM, P = 0.03), western blot for neutrophil gelatinase-associated lipocalin (NGAL) (control 3.3 + 1.8-fold vs ATX-304 1.2 + 0.55-fold, P = 0.002), and histological injury (control 3.5 + 0.59 vs ATX-304 2.7 + 0.74, P = 0.03). In TECs, pre-treatment with ATX-304 protected against cisplatin-mediated injury, as measured by lactate dehydrogenase release, MTS cell viability, and cleaved caspase 3 expression. ATX-304 protection against cisplatin was lost in AMPK-null murine embryonic fibroblasts. Metabolomic analysis in TECs revealed that ATX-304 (20 µM, 4 h) altered 66/126 metabolites, including fatty acids, tricarboxylic acid cycle metabolites, and amino acids. Metabolic studies of live cells using the XFe96 Seahorse analyzer revealed that ATX-304 increased the basal TEC oxygen consumption rate by 38%, whereas maximal respiration was unchanged. Thus, ATX-304 protects against cisplatin-mediated kidney injury via AMPK-dependent metabolic reprogramming, revealing a promising therapeutic strategy for AKI.

Introduction: Renal Replacement Therapy (RRT) is associated with hypotension. However, its impact on cardiac output (CO) is less understood. We aimed to describe current knowledge of CO monitoring and changes during RRT.Methods: We searched Medline, Embase and Cochrane from 01/01/2000 to 31/01/2023 using Covidence for studies of intermittent hemodialysis (IHD) and continuous RRT (CRRT) with at least three CO measurements during treatment. Two independent reviewers screened citations and a third resolved disagreements. The findings did not allow meta-analysis and are presented descriptively.Results: We screened 3285 articles and included 48 (37 during IHD, nine during CRRT, and two during both). Non-invasive devices (electrical conductivity techniques and finger cuff pulse contour) were the most common CO measurement techniques (21 studies). The median baseline cardiac index in IHD studies was 3 L/min/m2 (95% CI, 2.7 to 3.39). Among the 88 patient cohorts studied, a decrease in CO occurred in 63 (72%). In 16 cohorts, the decrease was severe (> 25%). Changes in blood pressure (BP) were not concordant in extent or direction with changes in CO. The decrease in CO correlated weakly with ultrafiltration rate (r = - 0.3, p = 0.05) and strongly with changes in systemic vascular resistance (SVR) (r = - 0.6, p < 0.001).Discussion/Conclusion: There are limited data on CO changes during RRT. However, a decrease in CO appeared common and was marked in one of five patient cohorts. Such decreases often occurred without BP changes and were associated with increased SVR.

Introduction: Hypotension is common during intermittent hemodialysis (IHD) and may be due to a decreased cardiac index (CI). However, no study has simultaneously and continuously measured CI and mean arterial pressure (MAP) to understand the prevalence, severity, and duration of CI decreases or relate them to MAP, blood volume (BV), and net ultrafiltration (NUF) rate. Methods: In a prospective, pilot and feasibility investigation, we studied 10 chronic IHD patients. We used the ClearSight System (TM) to continuously monitor CI and MAP; the CRIT-LINE (R) IV monitor to detect BV changes and collected data on NUF rate. Results: Device tolerance and compliance were 100%. All patients experienced at least >= 1 episode of severe CI decrease (>25% from baseline), with a median duration of 24 min (IQR 6-87) and of 68 min [14-106] for moderate decreases (>15% but <= 25% from baseline). Eight patients experienced a low CI state (<2.2 L/min/m2). The lowest CI was 0.9 L/min/m2 with a concomitant MAP of 94 mm Hg. When the fall in CI was severe, MAP increased in 58% of cases and remained stable in 28%. Overall, CI decreased by -0.55 L/min/m2 when BV decrease was moderate versus mild (p < 0.001) and by -0.8 L/min/m(2) when NUF rate was high versus low (p < 0.001). Conclusion: Continuous CI monitoring is feasible in IHD and shows frequent moderate-severe CI decreases, sometimes to low CI state levels. Such decreases are typically associated with markers of decreased intravascular volume status but not with a decrease in MAP, implying marked vasoconstriction.

BACKGROUND:Tunnelled central venous catheters (T-CVCs) are used globally as vascular access for patients on haemodialysis (HD) but are associated with increased sepsis, mortality, cost and length of hospitalisation compared with more permanent HD vascular access. The reasons for using T-CVC are varied and poorly understood. A significant and increasing proportion of incident HD patients in Victoria, Australia, have required T-CVC over the last decade. AIM:To explore reasons for a significant and increasing proportion of incident HD patients in Victoria, Australia, having required T-CVC over the last decade. METHODS:With rates of starting HD with definitive vascular access consistently below a Victorian quality indicator target of 70%, an online survey was developed to explore reasons why the rate remained lower than desired and to help inform future decisions about this quality indicator. The survey was completed by dialysis access coordinators over an 8-month period and involved all public nephrology services in Victoria. RESULTS:Of the 125 surveys completed, 101 incident HD patients had no attempt at permanent vascular access prior to T-CVC insertion. For almost half of these (48 patients), there was no active medical decision not to create permanent vascular access prior to commencing dialysis. Reasons for insertion of the T-CVC included deterioration of kidney function faster than anticipated, surgical referral being overlooked, complications related to peritoneal dialysis requiring a change in dialysis modality and changes to initial decisions regarding dialysis modality for kidney failure. CONCLUSIONS:These survey results provide an opportunity for quality improvement initiatives with respect to dialysis access planning and care.

Background Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0 center dot 9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. Methods BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). Findings Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0 center dot 74 [95% CI 0 center dot 66 to 0 center dot 84; p<0 center dot 0001]; adjusted risk difference 10 center dot 1% [95% CI 3 center dot 5 to 16 center dot 6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0 center dot 5%, 95% CI -1 center dot 8 to 0 center dot 9; p=0 center dot 48). Interpretation Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. Copyright (c) 2023 Published by Elsevier Ltd. All rights reserved.