Environmentally sustainable design guide for haemodialysis facilities: An Australian and New Zealand society of Nephrology initiative.

Haemodialysis facilities have a large environmental impact due to high energy, water and consumable usage by haemodialysis equipment. As climate change and natural resource scarcity escalate, all the while the number of people requiring dialysis increases, there is an urgent need for dialysis facilities that meet care needs while minimising environmental impact. To address this, the Australian and New Zealand Society of Nephrology engaged an environmental sustainability consulting practise to develop a best practise guide for the environmentally sustainable design and operation of haemodialysis facilities. Four opportunity areas were considered, namely energy, water, waste and resource recovery, and additional sustainability. A total of 28 environmental improvement initiatives were identified. The majority (n = 23) were general measures that could be applied across all healthcare settings, while five were specific to haemodialysis facilities. Recommendations were made regarding specific measures that should be undertaken and/or standards that must be met to achieve the intent of each initiative. These were stratified to enable their application to both existing dialysis facilities and new builds. The lifecycle stage of a haemodialysis facility to which each initiative applied was highlighted, as was its potential impact. This guide provides a tailored and comprehensive resource for the kidney care community to enable the integration of best practise sustainability considerations into both existing and new facilities. If broadly implemented, it has the potential to markedly improve the environmental impact of haemodialysis provision.

Our shared responsibility: the urgent necessity of global environmentally sustainable kidney care.

In response to Earth's accelerating climate crisis, we, an international group of nephrologists, call on our global community to unite and align kidney care in accordance with United Nation's 26th Conference of the Parties health sector principles. We announce a global and inclusive initiative, "GREEN-K": Global Environmental Evolution in Nephrology and Kidney Care, with a vision of "sustainable kidney care for a healthy planet and healthy kidneys" and mission to "promote and support environmentally sustainable and resilient kidney care globally through advocacy, education, and collaboration." A patient-centric approach that permits climate change mitigation and adaptation is proposed. Multi-stakeholder GREEN-K action and focus areas will include education, sustainable clinical care, and advances toward environmentally sustainable innovations, procurement, and infrastructure. Mindful of the disproportionately high climate impact of kidney therapies, we welcome the opportunity to work together in shared accountability to patients and Earth's natural systems.

Important lack of difference in tacrolimus and mycophenolic acid pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients.

AIM: To examine whether differences in tacrolimus and mycophenolic acid (MPA) pharmacokinetics contribute to the poorer kidney transplant outcomes experienced by Aboriginal Australians. METHODS: Concentration-time profiles for tacrolimus and MPA were prospectively collected from 43 kidney transplant recipients: 27 Aboriginal and 16 Caucasian. Apparent clearance (CL/F) and distribution volume (V/F) for each individual were derived from concentration-time profiles combined with population pharmacokinetic priors, with subsequent assessment for between-group difference in pharmacokinetics. In addition, population pharmacokinetic models were developed using the prospective dataset supplemented by previously developed structural models for tacrolimus and MPA. The change in NONMEM objective function was used to assess improvement in goodness of model fit. RESULTS: No differences were found between Aboriginal and Caucasian groups or empirical Bayes estimates, for CL/F or V/F of MPA or tacrolimus. However, a higher prevalence of CYP3A5 expressers (26% compared with 0%) and wider between-subject variability in tacrolimus CL/F (SD = 5.00 compared with 3.25 L/h/70 kg) were observed in the Aboriginal group, though these differences failed to reach statistical significance (p = .07 and p = .08). CONCLUSION: There were no differences in typical tacrolimus or MPA pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients. This means that Bayesian dosing tools developed to optimise tacrolimus and MPA dosing in Caucasian recipients may be applied to Aboriginal recipients. In turn, this may improve drug exposure and thereby transplant outcomes in this group. Aboriginal recipients appeared to have greater between-subject variability in tacrolimus CL/F and a higher prevalence of CYP3A5 expressers, attributes that have been linked with inferior outcomes.

Prolonged immunosuppression does not improve risk of sensitization or likelihood of retransplantation after kidney transplant graft failure.

The optimum approach towards immunosuppression withdrawal following kidney transplant failure is unclear. Prolonged weaning may be associated with reduced sensitization, less graft nephrectomy and greater likelihood of retransplantation, but conversely increased risk of infection, malignancy and death. We conducted a single-centre retrospective analysis of patients experiencing graft failure between 2007 and 2017, comparing rates of sensitization, retransplantation, nephrectomy, infection, malignancy and death between patients who had immunosuppression weaned over <90 vs. 90-180 vs. >180 days. Patient survival after immunosuppression withdrawal over <90 vs. 90-180 vs. >180 days was 73.3%, 72.1% and 80.4%, respectively (P = 0.35), with no differences in cPRA (80.06 vs. 81.21 vs. 85.42, P = 0.66) or retransplantation rate [24/31 (77.4%) vs. 21/35 (60.0%) vs. 22/36 (61.1%), P = 0.13]. There was significantly less nephrectomy after late immunosuppression cessation [10/42 (23.8%) vs. 7/42 (16.7%) vs. 3/43 (7.0%), P = 0.01] but no differences in infections or malignancy. On competing risk regression (death as competing risk) controlling for cofactors including age, nephrectomy and rejection, prolonged immunosuppression did not predict likelihood of retransplantation (SHR 1.000, P = 0.88). Prolonged immunosuppression withdrawal does not reduce sensitization or improve retransplantation rates but is associated with less nephrectomy. Immunosuppression withdrawal should be tailored to individual circumstances after graft failure.

Kidney transplant recipient perspectives on telehealth during the COVID-19 pandemic.

The COVID-19 pandemic has challenged the delivery of health services. Telehealth allows delivery of care without in-person contacts and minimizes the risk of vial transmission. We aimed to describe the perspectives of kidney transplant recipients on the benefits, challenges, and risks of telehealth. We conducted five online focus groups with 34 kidney transplant recipients who had experienced a telehealth appointment. Transcripts were thematically analyzed. We identified five themes: minimizing burden (convenient and easy, efficiency of appointments, reducing exposure to risk, limiting work disruptions, and alleviating financial burden); attuning to individual context (depending on stability of health, respect patient choice of care, and ensuring a conducive environment); protecting personal connection and trust (requires established rapport with clinicians, hampering honest conversations, diminished attentiveness without incidental interactions, reassurance of follow-up, and missed opportunity to share lived experience); empowerment and readiness (increased responsibility for self-management, confidence in physical assessment, mental preparedness, and forced independence); navigating technical challenges (interrupted communication, new and daunting technologies, and cognizant of patient digital literacy). Telehealth is convenient and minimizes time, financial, and overall treatment burden. Telehealth should ideally be available after the pandemic, be provided by a trusted nephrologist and supported with resources to help patients prepare for appointments.

Green dialysis survey: Establishing a baseline for environmental sustainability across dialysis facilities in Victoria, Australia.

AIM: The Green Dialysis Survey aimed to (i) establish a baseline for environmental sustainability (ES) across Victorian dialysis facilities; and (ii) guide future initiatives to reduce the environmental impact of dialysis delivery. METHODS: Nurse unit managers of all Victorian public dialysis facilities received an online link to the survey, which asked 107 questions relevant to the ES of dialysis services. RESULTS: Responses were received from 71/83 dialysis facilities in Victoria (86%), representing 628/660 dialysis chairs (95%). Low energy lighting was present in 13 facilities (18%), 18 (25%) recycled reverse osmosis water and seven (10%) reported use of renewable energy. Fifty-six facilities (79%) performed comingled recycling but only 27 (38%) recycled polyvinyl chloride plastic. A minority educated staff in appropriate waste management (n = 30;42%) or formally audited waste generation and segregation (n = 19;27%). Forty-four (62%) provided secure bicycle parking but only 33 (46%) provided shower and changing facilities. There was limited use of tele- or video-conferencing to replace staff meetings (n = 19;27%) or patient clinic visits (n = 13;18%). A minority considered ES in procurement decisions (n = 28;39%) and there was minimal preparedness to cope with climate change. Only 39 services (49%) confirmed an ES policy and few had ever formed a green group (n = 14; 20%) or were currently undertaking a green project (n = 8;11%). Only 15 facilities (21%) made formal efforts to raise awareness of ES. CONCLUSION: This survey provides a baseline for practices that potentially impact the environmental sustainability of dialysis units in Victoria, Australia. It also identifies achievable targets for attention.

Climate change and us: What nephrologists should know.

Global warming poses significant risks to human health and the planet. If allowed to continue unchecked, its consequences will be devastating. While all populations will be effected with time, vulnerable groups, including those with kidney disease, are likely to be at primary risk. This paper summarizes the current state of scientific knowledge relevant to climate change. It discusses the contribution of the health-care system, and particularly dialysis programmes, to greenhouse gas emissions, and pathways that exist for nephrologists to mitigate their environmental impact.

Population pharmacokinetics of tacrolimus in adult kidney transplant patients: impact of CYP3A5 genotype on starting dose.

OBJECTIVES: The aims of this study were to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant recipients, to use this model to compare cytochrome P450 3A5 (CYP3A5) genotype-based initial dosing of tacrolimus with standard per-kilogram-based dosing, and to predict the best starting dose of tacrolimus based on patient genotype to achieve a trough concentration between 6 and 10 µg/L by day 5 posttransplantation. METHODS: Population analysis was performed using the software program NONMEM. Tacrolimus dosing regimens were compared by predicting tacrolimus trough concentrations in a simulated data set by running NONMEM with population parameters fixed at the final model estimates. Data from 173 patients with 1554 tacrolimus concentration-time measurements were modeled. RESULTS: Tacrolimus disposition was well described by a 2-compartment model with first-order elimination and first-order absorption after a lag time. Patient CYP3A5 genotype (rs776746), weight, hematocrit, and postoperative day were identified as significant covariates effecting tacrolimus apparent oral clearance (CL/F), with higher CL/F in CYP3A5*1 allele carriers, heavier patients, patients with low hematocrit, and in the immediate posttransplantation period. Typical population estimates for tacrolimus CL/F in CYP3A5*1 allele carriers and noncarriers were 40.8 and 25.5 L/h, respectively. CONCLUSIONS: In patients carrying the CYP3A5*1 allele, a per-kilogram dose of 0.075 mg/kg twice daily seemed too much low with approximately 65% of simulated subjects predicted to achieve a trough below 6 µg/L at day 5 posttransplantation. To reduce the risk of under immunosuppression in the immediate posttransplantation period, carriers of a CYP3A5*1 allele are likely to benefit from a tacrolimus starting dose of either 10 mg or 0.115 mg/kg twice daily.

A practical limited sampling strategy to predict free prednisolone exposure and glycemia in kidney transplant recipients.

BACKGROUND: Despite significant interindividual variability in prednisolone pharmacokinetics and potentially serious consequences with inadequate or excessive exposure, monitoring of prednisolone levels is not employed to guide therapy. As ultrahigh-performance liquid chromatography-tandem mass spectrometry methods can now measure the active free fraction of prednisolone, this study aimed to evaluate the performance of 15 published limited sampling strategies (LSSs) for predicting free prednisolone exposure in adult kidney transplant recipients and to examine the relationship between free/total prednisolone exposure and plasma glucose. METHODS: The study was performed in 11 subjects without diabetes 3-4 weeks postkidney transplantation. Area under the concentration time curve profiles of total and free prednisolone from 0 to 12 hours postdose (AUC0₋12) were determined and compared with predicted AUC0₋12 values calculated from published LSSs. Venous glucose was measured concurrently with the 13 sampling time points. RESULTS: The mean (±SD) age of subjects was 52 ± 12 years, 5 were men and the median (interquartile range) daily prednisolone dose was 20.0 mg (20.0-22.5). Interindividual variation in dose-adjusted free and total prednisolone exposure was 1.9- and 3.2-fold, respectively. All 15 free prednisolone LSSs exhibited good correlation (r ≥ 0.83), with bias and imprecision less than 15%. An LSS incorporating 1.25- and 3-hour samples had the highest predictive power (r = 0.97, bias 1.2%, imprecision 5.6%). Free prednisolone AUC0₋12 correlated with peak glucose levels (r = 0.65, P = 0.037), as did predicted AUC0₋12 from 14/15 LSSs. CONCLUSIONS: Biologically active free prednisolone exposure can be accurately predicted postkidney transplantation by LSSs incorporating 2-point concentration sampling. Peak plasma glucose concentration correlated well with prednisolone exposure.

A differential impact of mycophenolic acid, prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients.

BACKGROUND: Soluble CD30 (sCD30) has been associated with rejection and graft loss in kidney transplantation, leading to the suggestion that sCD30 might be a useful biomarker to adjust immunosuppressant medication dosing. However, there has been minimal study of the influence of individual immunosuppressive drugs on sCD30 levels. AIM: To evaluate the influence of mycophenolic acid (MPA), prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients. METHODS: The sCD30 levels were measured pretransplant and 30 days posttransplant. Area under the concentration-time curve (AUC) for each drug was estimated on day 30 using validated, multiple regression-derived limited sampling strategies. RESULTS: One hundred twenty-five subjects were included. Median (interquartile range) sCD30 levels were lower on day 30 posttransplant compared with pretransplant [10.7 (3.7-20.1) pg/mL versus 66.5 (46.0-95.1) pg/mL; P < 0.0001]. On univariate analyses, day 30 sCD30 levels were negatively correlated with MPA exposure and positively correlated with tacrolimus exposure. Using multivariate logistic regression, higher tacrolimus exposure was independently associated with higher day 30 sCD30 levels (2.2 change in odds for an SD increase in tacrolimus AUC 0-12, P = 0.01; 5.5 change in odds for an SD increase in tacrolimus predose concentration, P < 0.0001). In contrast, MPA and total and free prednisolone exposures were not independently associated with sCD30 levels. CONCLUSIONS: The sCD30 levels are significantly reduced in the presence of combination immunosuppression but are differentially affected by different immunosuppressant agents. More research is required before introduction of sCD30 measurement into clinical practice can be considered.

A randomized controlled trial of oral heme iron polypeptide versus oral iron supplementation for the treatment of anaemia in peritoneal dialysis patients: HEMATOCRIT trial.

BACKGROUND: Preliminary clinical evidence suggests that heme iron polypeptide (HIP) might represent a promising, novel oral iron supplementation strategy in chronic kidney disease. The aim of this multi-centre randomized controlled trial was to determine the ability of HIP administration to augment iron stores in darbepoetin (DPO)-treated patients compared with conventional oral iron supplementation. METHODS: Adult peritoneal dialysis (PD) patients treated with DPO were randomized 1:1 to receive two capsules daily of either HIP or ferrous sulphate per os for 6 months. The primary outcome measure was transferrin saturation (TSAT). Secondary outcomes comprised serum ferritin, haemoglobin, DPO dose and responsiveness, and adverse events. RESULTS: Sixty-two patients were randomized to HIP (n = 32) or ferrous sulphate (n = 30). On intention-to-treat analysis, the median (inter-quartile range) TSAT was 22% (16-29) in the HIP group compared with 20% (17-26) in controls (P = 0.65). HIP treatment was not significantly associated with TSAT at 6 months on multivariable analysis (P = 0.95). Similar results were found on per-protocol analysis and subgroup analysis in iron-deficient patients. Serum ferritin levels at 6 months were significantly lower in the HIP group (P = 0.003), while the cost of HIP was 7-fold higher than that of ferrous sulphate. No other differences in secondary outcomes were observed. CONCLUSIONS: HIP showed no clear safety or efficacy benefit in PD patients compared with conventional oral iron supplements. The reduction in serum ferritin levels and high costs associated with HIP therapy suggest that this agent is unlikely to have a significant role in iron supplementation in PD patients.

Kidney transplant outcomes are related to tacrolimus, mycophenolic acid and prednisolone exposure in the first week.

This study analysed associations between tacrolimus, mycophenolic acid (MPA) and prednisolone exposures on day 4 and month 1 post kidney transplant and clinical outcomes. Area under the concentration-time curve (AUC) for each drug was estimated using validated multiple regression-derived limited sampling strategies. Multivariate logistic regression was used to associate drug exposure with clinical outcomes. One hundred and twenty subjects were studied. Between-subject variability in dose-adjusted exposure to each medication was high. Both day 4 tacrolimus and MPA exposures were independently predictive of delayed graft function (2.6 change in odds for a standard deviation (SD) increase in tacrolimus AUC(0-12) , P = 0.02; 0.23 change in odds for a SD increase in MPA AUC(0-12) , P = 0.02). Both day 4 MPA and total prednisolone exposures were independently predictive of rejection (0.20 change in odds for a SD increase in MPA AUC(0-12) , P = 0.04; 0.40 change in odds for a SD increase in total prednisolone AUC(0-6) , P = 0.03). Lowest tertile exposure to all three immunosuppressant medications imposed significantly higher odds of rejection [adjusted odds ratio 34.2 (95% CI 4.1, 284.4), P = 0.001]. This study highlights the importance of achieving early target exposure and suggests a potential role for individualized initial dosing or early therapeutic monitoring of all three immunosuppressive agents.

A limited sampling strategy for the simultaneous estimation of tacrolimus, mycophenolic acid and unbound prednisolone exposure in adult kidney transplant recipients.

AIM: The aim of this study was to develop a limited sampling strategy (LSS) for the simultaneous estimation of exposure to tacrolimus, mycophenolic acid and unbound prednisolone in adult kidney transplant recipients. METHODS: Tacrolimus, mycophenolic acid and unbound prednisolone area under the concentration-time curve profiles from 0 to 12 h post dose (AUC(0-12)) were collected from 20 subjects. Multiple linear regression analyses were performed to develop a LSS enabling the simultaneous estimation of exposure to all three drugs. Median percentage prediction error and median absolute percentage prediction error were calculated via jackknife analysis to evaluate bias and imprecision. RESULTS: LSS showed superior ability to predict exposure compared with single concentration-time points. A LSS incorporating concentration measurements at 0.5 h (C(0.5)), 2 h (C(2)) and 4 h (C(4)) post dose displayed acceptable predictive ability for all three drugs. CONCLUSION: This LSS may serve as a useful research tool for further investigation of the utility of concentration monitoring of these medications.

Comparison of free plasma versus saliva mycophenolic acid exposure following mycophenolate mofetil administration in adult kidney transplant recipients.

Therapeutic monitoring (TDM) of mycophenolic acid (MPA) has the potential to improve drug inefficacy and toxicities in kidney transplantation. However, measurement of plasma MPA concentrations is laborious and invasive. This study examined the utility of saliva compared with plasma based TDM of MPA. Paired blood and saliva samples were collected from 47 adult kidney transplant recipients pre- and at 1-, 2-, and 4-hours post mycophenolate mofetil administration. No relationship was observed between saliva MPA concentrations and either total or free plasma MPA concentrations (p > 0.05). This suggests that saliva is a poor direct marker of plasma MPA concentrations and therefore should not be used for MPA TDM.