The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury.

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.

Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

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 (0·9% 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 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). 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 -0·5%, 95% CI -1·8 to 0·9; p=0·48). 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. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

Tunnelled central venous catheters for incident haemodialysis patients: a Victorian survey exploring reasons for use.

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.

Mutation of regulatory phosphorylation sites in PFKFB2 does not affect the anti-fibrotic effect of metformin in the kidney.

The anti-fibrotic effect of metformin has been widely demonstrated. Fibrosis in the kidney after injury is associated with reduced expression of genes involved in both fatty acid and glycolytic energy metabolism. We have previously reported that the anti-fibrotic effect of metformin requires phosphoregulation of fatty acid oxidation by AMP-activated protein kinase (AMPK). To determine whether metformin also acts via regulation of glycolysis, we mutated regulatory phosphosites in the PFKFB2 isoform of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB2), a key regulator of glycolysis in the kidney. Mice with inactivating knockin (KI) mutations of the phosphorylation sites in PFKFB2 (PFKFB2 KI mice), which reduces the ability to increase the rate of glycolysis following stimulation, were used. Metformin was administered via drinking water to mice with a unilateral ureteric obstruction (UUO) model of renal fibrosis. In the PFKFB2 KI mice treated with metformin, there was decreased fibrosis and macrophage infiltration following UUO as assessed by Western blot for fibronectin and RT-PCR for α-smooth muscle actin, collagen 3, and F4.80, and confirmed by histology. Expression of the inducible PFKFB3 isoform was increased with metformin in UUO in both WT and PFKFB2 KI mice. There was no significant difference between WT and PFKFB2 KI mice treated with metformin in the degree of fibrosis following UUO in any of the Western blot or RT-PCR parameters that were measured. These data show that inhibition of the regulation of glycolysis by PFKFB2 does not diminish the anti-fibrotic effect of metformin in a model of renal fibrosis.

Baseline Characteristics and Representativeness of Participants in the BEST-Fluids Trial: A Randomized Trial of Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation.

Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail. Methods: We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients. Results: During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences. Conclusions: BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.

Blocking AMPK signalling to acetyl-CoA carboxylase increases cisplatin-induced acute kidney injury and suppresses the benefit of metformin.

BACKGROUND: Acute kidney injury (AKI) is accompanied by dysregulation of cellular energy metabolism and accumulation of intracellular lipid. Phosphorylation of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) inhibits fatty acid synthesis and promotes fatty acid oxidation (FAO), vital for kidney tubular epithelial cells (TECs). The diabetes drug metformin is protective in models of AKI; however, it is not known whether ACC phosphorylation plays a role. METHODS: Cisplatin-induced AKI (CI-AKI) was established in ACC1/2 double knock-in (ACC1/2DKI) mice, harbouring mutations that disrupt fatty acid metabolism, and the role of metformin was studied in this model. Outcomes measured included serum biochemistry, expression of kidney injury markers such as neutrophil gelatinase-associated lipocalin (NGAL), and metabolomic analysis. FINDINGS: ACC1/2DKI mice demonstrated more severe CI-AKI than wild type (WT), as assessed by serum urea and creatinine, histological injury, and expression of NGAL and interleukin-6. Metformin protected against AKI in WT mice, shown by reduced NGAL, but this effect was absent in ACC1/2DKI mice. In cultured TECs exposed to cisplatin, metformin reduced expression of cleaved caspase-3, however, this effect was diminished in ACC1/2DKI TECs. Analysis of kidney polar metabolites found numerous differences between metformin-treated CI-AKI in ACC1/2DKI and WT mice, involving multiple pathways of amino acid, nucleoside, and energy metabolism. INTERPRETATION: Severity of CI-AKI is exacerbated by the inability to regulate metabolism via phosphorylation of ACC. ACC phosphorylation contributes to the protective effect of metformin against AKI, influencing multiple mechanisms involved in the pathogenesis of kidney injury.

Lower versus higher starting tacrolimus dosing in kidney transplant recipients.

Achieving therapeutic tacrolimus levels is an essential component of balancing immunosuppression in kidney transplantation. At our institution, the starting tacrolimus dose was reduced from .075 mg/kg BD (higher dose [HD]) to .050 mg/kg BD (lower dose [LD]), to better achieve our target level of 6-10 µg/L in the early posttransplant period. Kidney transplant recipients (KTRs) transplanted 1-year before (HD: n = 64) and after (LD: n = 63) the starting dose reduction were retrospectively compared. Achieved tacrolimus levels were significantly lower in the LD group during the first 14 days posttransplant, but not at day 21 or day 28. A higher proportion of LD KTRs achieved therapeutic levels (day 1-3: 36.1% vs. 18.8%; day 4-7: 50.8% vs. 40.6%, day 8-14: 83.6% vs. 71.7%), while the HD KTRs were more likely to have supratherapeutic levels. Tacrolimus dose was significantly lower on day 5 compared to day 0 in the HD group but similar in the LD group. Rates of delayed graft function, posttransplant diabetes, and treated rejection at 6 months and graft outcomes at 3 years were all similar. Lowering the starting tacrolimus dose increased the proportion of KTRs achieving therapeutic range and minimized dose changes early posttransplant without an impact on clinical outcomes.

COVID-19 beliefs and vaccination uptake in dialysis patients: lessons from an anonymous patient survey.

BACKGROUND: There is a lack of data on how to best optimise uptake of COVID-19 vaccination in dialysis patients. AIM: To understand attitudes and beliefs about COVID-19 and vaccination uptake in dialysis patients. METHODS: A single-centre, cross-sectional study involving a clinical audit and an anonymous survey of adult maintenance dialysis patients was conducted. RESULTS: The vaccination uptake during the study period was 77.5% at least single dose, compared with 70% in Victoria during the same period. Participants were more likely to be vaccinated if they believed COVID-19 was a serious problem that is worse for people on dialysis. Those unvaccinated were more likely to overestimate the risk of vaccine complications and less likely to have the annual influenza vaccine. Despite over 80% of participants agreeing that they would have the vaccine if recommended by their nephrologist, less than 40% reported receiving information from this source. A predominant reason for vaccine hesitancy was concern regarding vaccine safety. Over 60% of those who were unvaccinated were still open to the vaccine, indicating a significant opportunity to improve vaccination rates through medical consultation and direction. CONCLUSIONS: Vaccine hesitancy for COVID-19 in dialysis patients associates with less informed health beliefs, both about the disease and the risks of vaccination. Patients are more likely to get vaccinated if it is recommended by their nephrologist. Clinicians caring for dialysis patients have a key role in providing high-quality education and advice, representing an urgent opportunity for improvement in vaccination uptake against COVID-19.

Bone microarchitecture and estimated failure load are deteriorated whether patients with chronic kidney disease have normal bone mineral density, osteopenia or osteoporosis.

INTRODUCTION: Measurement of bone mineral density (BMD) is recommended in patients with chronic kidney disease (CKD). However, most persons in the community and most patients with CKD have osteopenia, suggesting fracture risk is low. Bone loss compromises bone microarchitecture which increases fragility disproportionate to modest deficits in BMD. We therefore hypothesized that patients with CKD have reduced estimated failure load due to deterioration in microarchitecture irrespective of whether they have normal femoral neck (FN) BMD, osteopenia or osteoporosis. METHODS: We measured distal tibial and distal radial microarchitecture in 128 patients with CKD and 275 age- and sex-matched controls using high resolution peripheral quantitative computed tomography, FN-BMD using bone densitometry and estimated failure load at the distal appendicular sites using finite element analysis. RESULTS: Patients versus controls respectively had: lower tibial cortical area 219 (40.7) vs. 237 (35.3) mm2, p = 0.002, lower cortical volumetric BMD 543 (80.7) vs. 642 (81.7) mgHA/cm3 due to higher porosity 69.6 (6.19) vs. 61.9 (6.48)% and lower matrix mineral density 64.2 (0.62) vs. 65.1 (1.28)%, lower trabecular vBMD 92.2 (41.1) vs. 149 (43.0) mgHA/cm3 due to fewer and spatially disrupted trabeculae, lower FN-BMD 0.78 (0.12) vs. 0.94 (0.14) g/cm2 and reduced estimated failure load 3825 (1152) vs. 5778 (1467) N, all p < 0.001. Deterioration in microarchitecture and estimated failure load was most severe in patients and controls with osteoporosis. Patients with CKD with osteopenia and normal FN-BMD had more deteriorated tibial microarchitecture and estimated failure load than controls with BMD in the same category. In univariate analyses, microarchitecture and FN-BMD were both associated with estimated failure load. In multivariable analyses, only microarchitecture was independently associated with estimated failure load and accounted for 87% of the variance. CONCLUSIONS: Bone fragility is likely to be present in patients with CKD despite them having osteopenia or normal BMD. Measuring microarchitecture may assist in targeting therapy to those at risk of fracture.

Effect of a medium cut-off dialyzer on protein-bound uremic toxins and mineral metabolism markers in patients on hemodialysis.

INTRODUCTION: Hemodialysis (HD) with medium cut-off (MCO) dialyzers may expand molecular clearance, predominantly larger middle molecules (molecular weight 25-60 kDa). However, the impact of MCO dialyzers on long-term clearance of various other components of the uremic milieu is unknown. The tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HemoDialysis patients (REMOVAL-HD) provided an opportunity to assess the effect of MCO dialyzers on protein-bound uremic toxins and novel markers of mineral metabolism. METHODS: This exploratory sub-study of REMOVAL-HD evaluated changes in protein-bound solutes (total and free indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) and mineral metabolism markers (intact fibroblast growth factor-23 [iFGF23], fetuin-A and endogenous calciprotein particles [CPP-1 and CPP-2]). Mid-week, pre-HD serum samples were collected at baseline and after 12 and 24 weeks of MCO use in stable adult patients. Change from baseline to Week 12 and 24 was estimated using linear mixed effects models. FINDINGS: Eighty-nine participants were studied (mean age 67 ± 15 years, 38% female, 51% diabetic, median urine output 200 ml/24 h). Serum iFGF23 was reduced at Week 12 compared to baseline (-26.8% [95%CI -39.7, -11.1], p = 0.001), which was sustained at Week 24 (-21.7% [95%CI -35.7, -4.5], p = 0.012). There was no significant change in serum IS, PCS, fetuin-A, CPP-1, or CPP-2. DISCUSSION: The use of a MCO dialyzer over 24 weeks was associated with a sustained reduction in FGF23, while other measured components of the uremic milieu were not significantly altered. Further studies are required to determine whether FGF23 reduction is associated with improved patient outcomes.

Dialysis and driving: an anonymous survey of patients receiving dialysis for end-stage kidney disease.

BACKGROUND: Driving is a complex task requiring multiple cognitive domains and the musculoskeletal system. Cognitive dysfunction is associated with driving impairment. Dialysis patients are known to have a high prevalence of cognitive impairment and other comorbidities, and may be at risk of driving impairment. No Australian guidelines address driving safety in dialysis patients. AIMS: To estimate the proportion of dialysis patients who were driving and those at risk of driving impairment, and to investigate the agreement between objective and subjective markers of risk. METHODS: This single-centre study involved dialysis patients voluntarily completing two questionnaires relating to risk of driving impairment; the first questionnaire focussed on objective markers, and the second questionnaire focussed on subjective markers. Risk of driving impairment was established using pre-determined criteria, and the agreement between objective and subjective markers was estimated using Cohen kappa. RESULTS: A total of 44.8% (99/221) of patients participated; 76.8% (76/99) of participants were driving, and 76.3% (58/76) of drivers were at risk of driving impairment. Factors associated with at-risk driving included post dialysis dizziness, leg weakness or numbness, falling asleep while driving and hypoglycaemia. Sixteen patients reported collisions since commencing dialysis. The questionnaires displayed slight agreement (Cohen kappa = 0.20) between objective and subjective markers. CONCLUSIONS: Dialysis patients are at risk of driving impairment based on self-reported questionnaire responses. Discrepancies between patients' perceptions and objective markers were apparent. Further research into appropriate risk assessments, as well as development of guidelines to aid in determining driving safety in dialysis patients, is needed.

Relationship between residual kidney function and symptom burden in haemodialysis patients.

BACKGROUND: Residual kidney function (RKF) has been associated with improved solute clearance and survival in haemodialysis (HD) patients. However, whether RKF impacts symptom burden in HD patients is unknown. AIMS: To determine the prevalence of RKF in HD patients and to explore associations between higher levels of RKF with symptom burden, as well as clinical and biochemical parameters. METHODS: This is a single-centre, retrospective, observational study. RKF was assessed as urea clearance (KRU) by interdialytic urine collection. Symptom burden was measured using the palliative care outcome scale renal questionnaire. RESULTS: A total of 90 maintenance HD patients was recruited; 31.9% had KRU ≥1 mL/min/1.73 m2 . Patients with KRU ≥1 mL/min/1.73 m2 reported fewer symptoms (5.3 ± 3.5 vs 7.7 ± 3.8) (P = 0.011), including less shortness of breath (15% vs 55%) (P = 0.0013) and vomiting (0% vs 30%) (P = 0.0016). Higher RKF was associated with lower ß2 -microglobilin (P < 0.0001), and lower serum potassium (P = 0.02), but no difference in phosphate, haemoglobin, C-reactive protein or serum albumin. CONCLUSION: Higher RKF was significantly associated with fewer symptoms, and lower serum ß2 -microglobulin and potassium, suggesting that strategies to preserve RKF may be beneficial.

Outcomes of patients commencing peritoneal dialysis with and without back-up arteriovenous fistulas.

BACKGROUND: Transitions from peritoneal dialysis (PD) to haemodialysis (HD) are often unpredictable and central venous catheters (CVCs) are frequently required. Early studies found few back-up arteriovenous fistulas (bAVFs) were ever used. The PD population's characteristics have changed over time which may have altered the likelihood of bAVFs being used. This study aimed to report use of, and outcomes associated with, bAVFs in a contemporary cohort of peritoneal dialysis patients. METHOD: A single-centre, retrospective study of PD patients commencing dialysis between 2006-2016, stratified according to presence/absence of bAVF. RESULTS: One hundred seventy-six patients were included-82 with bAVF, 94 without bAVF-of whom 156 transitioned off PD. Transitions were to HD (49%), transplantation (23%), death (15%) and renal-recovery (1%). 51% of bAVFs were successfully used and 82% of bAVFs were patent when required. Median time from creation to bAVF use was 2.5 years. More patients with a bAVF transitioned to HD (62 vs 38%, p < 0.005). However, CVC requirement at the time of transition to HD was much less common in the bAVF group (18 vs 83%, p < 0.0001), such that the overall risk of requiring a CVC was significantly lower in the bAVF group (11 vs 31%, p < 0.005). Rates of returning to PD amongst patients who transitioned to HD with a CVC or an AVF were similar (19 vs 26%, p = 0.16). CONCLUSIONS: In this cohort of PD patients, utilisation of back-up arteriovenous fistulas was higher than previously reported, and presence of a back-up arteriovenous fistula was associated with a lower rate of future CVC use.

Mutation of regulatory phosphorylation sites in PFKFB2 worsens renal fibrosis.

Fatty acid oxidation is the major energy pathway used by the kidney, although glycolysis becomes more important in the low oxygen environment of the medulla. Fatty acid oxidation appears to be reduced in renal fibrosis, and drugs that reverse this improve fibrosis. Expression of glycolytic genes is more variable, but some studies have shown that inhibiting glycolysis reduces renal fibrosis. To address the role of glycolysis in renal fibrosis, we have used a genetic approach. The crucial control point in the rate of glycolysis is 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase. Phosphorylation of the kidney isoform, PFKFB2, on residues Ser468 and Ser485 stimulates glycolysis and is the most important mechanism regulating glycolysis. We generated transgenic mice with inactivating mutations of Ser468 and Ser485 in PFKFB2 (PFKFB2 KI mice). These mutations were associated with a reduced ability to increase glycolysis in primary cultures of renal tubular cells from PFKFB2 KI mice compared to WT cells. This was associated in PFKFB2 KI mice with increased renal fibrosis, which was more severe in the unilaternal ureteric obstruction (UUO) model compared with the folic acid nephropathy (FAN) model. These studies show that phosphorylation of PFKFB2 is important in limiting renal fibrosis after injury, indicating that the ability to regulate and maintain adequate glycolysis in the kidney is crucial for renal homeostasis. The changes were most marked in the UUO model, probably reflecting a greater effect on distal renal tubules and the greater importance of glycolysis in the distal nephron.

Study Protocol for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): a pragmatic, registry-based, multi-center, double-blind, randomized controlled trial evaluating the effect of intravenous fluid therapy with Plasma-Lyte 148 versus 0.9% saline on delayed graft function in deceased donor kidney transplantation.

BACKGROUND: Delayed graft function, the requirement for dialysis due to poor kidney function post-transplant, is a frequent complication of deceased donor kidney transplantation and is associated with inferior outcomes and higher costs. Intravenous fluids given during and after transplantation may affect the risk of poor kidney function after transplant. The most commonly used fluid, isotonic sodium chloride (0.9% saline), contains a high chloride concentration, which may be associated with acute kidney injury, and could increase the risk of delayed graft function. Whether using a balanced, low-chloride fluid instead of 0.9% saline is safe and improves kidney function after deceased donor kidney transplantation is unknown. METHODS: BEST-Fluids is an investigator-initiated, pragmatic, registry-based, multi-center, double-blind, randomized controlled trial. The primary objective is to compare the effect of intravenous Plasma-Lyte 148 (Plasmalyte), a balanced, low-chloride solution, with the effect of 0.9% saline on the incidence of delayed graft function in deceased donor kidney transplant recipients. From January 2018 onwards, 800 participants admitted for deceased donor kidney transplantation will be recruited over 3 years in Australia and New Zealand. Participants are randomized 1:1 to either intravenous Plasmalyte or 0.9% saline peri-operatively and until 48 h post-transplant, or until fluid is no longer required; whichever comes first. Follow up is for 1 year. The primary outcome is the incidence of delayed graft function, defined as dialysis in the first 7 days post-transplant. Secondary outcomes include early kidney transplant function (composite of dialysis duration and rate of improvement in graft function when dialysis is not required), hyperkalemia, mortality, graft survival, graft function, quality of life, healthcare resource use, and cost-effectiveness. Participants are enrolled, randomized, and followed up using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. DISCUSSION: If using Plasmalyte instead of 0.9% saline is effective at reducing delayed graft function and improves other clinical outcomes in deceased donor kidney transplantation, this simple, inexpensive change to using a balanced low-chloride intravenous fluid at the time of transplantation could be easily implemented in the vast majority of transplant settings worldwide. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12617000358347. Registered on 8 March 2017. ClinicalTrials.gov: NCT03829488. Registered on 4 February 2019.

A tRial Evaluating Mid Cut-Off Value Membrane Clearance of Albumin and Light Chains in HemoDialysis Patients: A Safety Device Study.

BACKGROUND: A new class of dialysis membrane, the mid cut-off (MCO) dialyzer, has been developed to improve the clearance of uremic toxins in hemodialysis (HD). The a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HemoDialysis patients (REMOVAL-HD) study aimed to determine if regular use of MCO dialyzer was safe and specifically did not result in a significant loss of albumin. METHODS: This investigator initiated, crossover, longitudinal, device study was conducted across 9 centers in Australia and New Zealand (n = 89). Participants had a 4-week wash-in with high-flux HD, followed by 24-week intervention with MCO HD and a subsequent 4-week wash-out with high-flux HD. The primary outcome was change in serum albumin between weeks 4 and 28. Secondary outcomes included trends in serum albumin, changes in kappa- and lambda-free light chains (FLC), 6-min walk test (6MWT), malnutrition inflammation score (MIS), restless legs score and quality of life. RESULTS: Participants had a mean age of 66 ± 14 years, 62% were men, 45% were anuric, and 51% had -diabetes. There was no reduction in serum albumin following treatment with MCO HD (mean reduction -0.7 g/L, 95% CI -1.5 to 0.1). A sustained, unexplained reduction in serum albumin (>25%) was not observed in any participant. A reduction in FLC was observed 2 weeks into MCO HD (lambda-FLC: Δ -9.1 mg/L, 95% CI -14.4 to -3.7; kappa-FLC: Δ -5.7 mg/L, 95% CI -9.8 to -1.6) and was sustained for the rest of the study intervention. Both FLC increased after the cessation of MCO use. There was no improvement in restless legs symptoms, quality of life, 6MWT or MIS scores. CONCLUSIONS: Regular HD using the MCO dialyzer did not result in a significant fall in serum albumin. There were no effects on quality of life, functional status or nutrition. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number (ANZCTRN) 12616000804482.

Changes in Symptom Burden in Dialysis Patients Assessed Using a Symptom-Reporting Questionnaire in Clinic.

INTRODUCTION: To determine the prevalence, severity, and change in symptoms experienced by dialysis patients following the introduction of use of a symptom-reporting questionnaire in nephrology clinic. METHODS: This is an observational study of 160 prevalent dialysis patients. Palliative care Outcome Scale symptom (POS-renal) questionnaires modified for patients with end-stage kidney disease were completed at baseline and follow-up (median 3 months), with results available to nephrologists at clinic appointments. FINDINGS: The baseline prevalence of individual symptoms ranged from 15% to 66%. The most common symptoms were lack of energy (66%) and poor mobility (58%). The median number of symptoms was 7/17 (interquartile range [IQR]: 4-10). Forty-nine percent of patients rated at least 1 symptom as severe or overwhelming. At follow-up, the median number of symptoms experienced was unchanged at 7/17 (IQR: 3-10). However, there was considerable flux in symptom severity. On average, individual symptoms that were present at baseline improved in 56% of patients and worsened in 18%; only 26% had stable symptom severity. Individual symptoms newly occurred in 8% to 20% of patients between time points, with 77% of patients experiencing at least 1 new symptom. The percent of patients rating at least 1 symptom as severe or overwhelming was reduced from 49% to 39% (P = .040). CONCLUSIONS: Use of the POS-renal questionnaire identified a high symptom burden. The presence and severity of symptoms changed dramatically over a short follow-up period, highlighting the need for regular surveillance of symptoms in the dialysis population. Routine use of a symptom questionnaire in clinic may be useful for the identification and management of symptoms in dialysis patients.

Risk factors for foot ulceration in adults with end-stage renal disease on dialysis: a prospective observational cohort study.

BACKGROUND: Dialysis patients experience high rates of foot ulceration. Although risk factors for ulceration have been extensively studied in patients with diabetes, there is limited high-quality, longitudinal evidence in the dialysis population. Therefore, this study investigated risk factors for foot ulceration in a stable dialysis cohort. METHODS: We prospectively collected clinical, demographic, health status, and foot examination information on 450 adults with end-stage renal disease from satellite and home-therapy dialysis units in Melbourne, Australia over 12 months. The primary outcome was foot ulceration. Cox proportional hazard modelling and multinomial regression were used to investigate risk factors. RESULTS: Among 450 dialysis patients (mean age, 67.5 years; 64.7% male; 94% hemodialysis; 50.2% diabetes), new cases of foot ulceration were identified in 81 (18%) participants. Overall, risk factors for foot ulceration were neuropathy (HR 3.02; 95% CI 1.48 to 6.15) and previous ulceration (HR 2.86; CI 1.53 to 5.34). In those without history of ulceration, nail pathology (RR 3.85; CI 1.08 to 13.75) and neuropathy (RR 2.66; CI 1.04 to 6.82) were risk factors. In those with history of ulceration, neuropathy (RR 11.23; CI 3.16 to 39.87), peripheral arterial disease (RR 7.15; CI 2.24 to 22.82) and cerebrovascular disease (RR 2.08; CI 1.04 to 4.16) were risk factors. There were 12 (2.7%) new amputations, 96 (21.3%) infections, 24 (5.3%) revascularizations, 42 (9.3%) foot-related hospitalizations, and 52 (11.6%) deaths. CONCLUSIONS: Neuropathy and previous ulceration are major risk factors for foot ulceration in dialysis patients. Risk factors differ between those with and without prior ulceration. The risk factors identified will help to reduce the incidence of ulceration and its associated complications.

Absence of the ß1 subunit of AMP-activated protein kinase reduces myofibroblast infiltration of the kidneys in early diabetes.

Activation of the heterotrimeric energy-sensing kinase AMP-activated protein kinase (AMPK) has been reported to improve experimental diabetic kidney disease. We examined the effect of type 1 diabetes in wild-type (WT) mice and mice lacking the ß1 subunit of AMPK (AMPK ß1-/- mice), which have reduced AMPK activity in kidneys and other organs. Diabetes was induced using streptozotocin (STZ) and the animals followed up for 4 weeks. Hyperglycaemia was more severe in diabetic AMPK ß1-/- mice, despite the absence of any difference in serum levels of insulin, adiponectin and leptin. There was no change in AMPK activity in the kidneys of diabetic WT mice by AMPK activity assay, or phosphorylation of either the αT172 activation site on the α catalytic subunit of AMPK or the AMPK-specific phosphosite S79 on acetyl CoA carboxylase 1 (ACC1). Phosphorylation of the inhibitory αS485 site on the α subunit of AMPK was significantly increased in the WT diabetic mice compared to non-diabetic controls. Despite increased plasma glucose levels in the diabetic AMPK ß1-/- mice, there were fewer myofibroblasts in the kidneys compared to diabetic WT mice, as evidenced by reduced α-smooth muscle actin (α-SMA) protein by Western blot, mRNA by qRT-PCR and fewer α-SMA-positive cells by immunohistochemical staining. Albuminuria was also reduced in the AMPK ß1-/- mice. In contrast to previous studies, therefore, myofibroblasts were reduced in the kidneys of AMPK ß1-/- diabetic mice compared to diabetic WT mice, despite increased circulating glucose, suggesting that AMPK can worsen renal fibrosis in type 1 diabetes.