Improving Diverse and Equitable Involvement of Patients and Caregivers in Research in CKD: Report of a Better Evidence and Translation-Chronic Kidney Disease (BEAT-CKD) Workshop.

Patient and caregiver involvement can enhance the uptake and impact of research, but the involvement of patients and caregivers who are underserved and marginalized is often limited. A better understanding of how to make involvement in research more broadly accessible, supportive, and inclusive for patients with chronic kidney disease (CKD) and caregivers is needed. We conducted a national workshop involving patients, caregivers, clinicians, and researchers from across Australia to identify strategies to increase the diversity of patients and caregivers involved in CKD research. Six themes were identified. Building trust and a sense of safety was considered pivotal to establishing meaningful relationships to support knowledge exchange. Establishing community and connectedness was expected to generate a sense of belonging to motivate involvement. Balancing stakeholder goals, expectations, and responsibilities involved demonstrating commitment and transparency by researchers. Providing adequate resources and support included strategies to minimize the burden of involvement for patients and caregivers. Making research accessible and relatable was about nurturing patient and caregiver interest by appealing to intrinsic motivators. Adapting to patient and caregiver needs and preferences required tailoring the approach for individuals and the target community. Strategies and actions to support these themes may support more diverse and equitable involvement of patients and caregivers in research in CKD.

Erratum: This Article Corrects: "Behind the Curtain: The Nurse's Voice in Assessment of Residents in the Emergency Department".

[This corrects the article on p. 23 in vol. 20, PMID: 30643597.].

Behind the Curtain: The Nurse's Voice in Assessment of Residents in the Emergency Department.

Introduction: Feedback provides valuable input for improving physician performance. Conventionally, feedback is obtained from attending physicians; however, residents work in close contact with other members of the care team, especially nurses. Nurses may have more opportunity to directly observe trainees. In addition, they may value different behaviors and provide unique feedback. The objective of this study was to examine the nurse's perspective of resident performance in the emergency department. Methods: This was a retrospective, mixed-methods study of nursing assessments of residents using a five-point scale from 1 (unsatisfactory) to 5 (outstanding) and providing comments. Analysis included descriptive statistics of the quantitative assessments and content analysis of the nursing comments by a group of attendings, residents, and nurses. Results: Nurses assessed residents as above expectation or outstanding, especially for the categories of "How would you rate this resident's attitude?" (65%) and "Is this resident a team player?" (64%). Content analysis of the comments yielded nine themes including being kind, communication with nurses, being a team player, work ethic and efficiency, and respect for other team members. Of the comments made, 50% provided positive feedback, and the majority of comments (80%) were determined to be actionable. Conclusion: Our data indicate that nurses provide feedback on residents' kindness, efficiency and communication. These two aspects of interacting in the healthcare setting may not be highlighted in conventional, attending provider feedback, yet they are clearly noted by the nurse's voice.

NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation.

BACKGROUND: Pregnane X, encoded by the gene NR112, is a nuclear receptor whose primary role is to promote the detoxification and clearance of drugs and other foreign compounds from the body. AIM: The aim of this study was to analyze associations between NR1I2 polymorphisms, immunosuppressant drug exposure, and clinical outcomes in adult kidney transplant recipients. METHODS: Exposures to tacrolimus, mycophenolic acid, and total and free prednisolone were estimated at month 1 posttransplant using validated multiple regression-derived limited sampling strategies. RESULTS: In the 158 subjects studied, median (interquartile range) dose-adjusted exposure to tacrolimus was significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) µg·h/L/mg versus 15 (9, 24) µg·h/L/mg; P =0.0007]. Using multivariable logistic regression, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38% vs 18%, P=0.005) and possession of the NR1I2 8055T allele imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95% confidence interval, 1.33-7.73]; P=0.006). No significant difference in geometric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly, independently associated with total or free prednisolone or MPA exposure. CONCLUSIONS: These data demonstrate an impact of pregnane X receptor polymorphisms on tacrolimus pharmacokinetics. Association of the 8055T allele with BK viremia suggests clinically significant "overimmunosuppression" in individuals with this genotype.

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.

Evaluation of limited sampling strategies for total and free prednisolone in adult kidney transplant recipients.

PURPOSE: The aims of this study were to evaluate the predictive performances of all previously derived limited sampling strategies (LSSs) for total prednisolone, and to derive LSSs for free prednisolone in an independent cohort of adult kidney transplant recipients. METHODS: Total and free prednisolone area under the concentration-time curve profiles from 0 to 12 hours post-dose (AUC(0-12)) were collected from 20 subjects. All previously published total prednisolone LSSs were identified from the literature. Free prednisolone LSSs were developed using multiple linear regression analyses. AUC predicted by each of the LSSs was compared with AUC(0-12). Median percentage prediction error (MPPE) and median absolute percentage prediction error (MAPE) were calculated to evaluate bias and imprecision. RESULTS: Total dose-adjusted prednisolone exposure varied 5-fold among study participants, while free dose-adjusted prednisolone exposure varied 3-fold. Correlation (r²) between total and free prednisolone AUC(0-12) was 0.79 (p = <0.0001) for the entire study cohort. This correlation was poorer in those early compared with late post-transplant (r² = 0.42 (p = 0.04) versus r² = 0.59 (p = 0.009) respectively). Ten previously published LSSs for total prednisolone and 15 derived LSSs for free prednisolone performed with acceptable levels of bias and imprecision (<15%). Of the free prednisolone LSSs, an equation incorporating 0.25-, 2- and 4-h concentrations showed the highest predictive power (AUC0-12 = -17.20 + 1.18 × C0.25 + 2.75 × C2 + 4.45 × C4; MPPE = 0.1%, MAPE = 4.6%). CONCLUSIONS: Wide between-subject variability in drug exposure suggests a role for TDM. LSSs can accurately estimate both total and free prednisolone AUC(0-12). However, given the poor correlation observed between the two parameters, our data suggest that free prednisolone LSSs may be preferable.

Evaluation of limited sampling methods for estimation of tacrolimus exposure in adult kidney transplant recipients.

AIMS: To examine the predictive performance of limited sampling methods for estimation of tacrolimus exposure in adult kidney transplant recipients. METHODS: Twenty full tacrolimus area under the concentration-time curve from 0 to 12 h post-dose (AUC(0-12)) profiles (AUCf) were collected from 20 subjects. Predicted tacrolimus AUC(0-12) (AUCp) was calculated using the following: (i) 42 multiple regression-derived limited sampling strategies (LSSs); (ii) five population pharmacokinetic (PK) models in the Bayesian forecasting program TCIWorks; and (iii) a Web-based consultancy service. Correlations (r(2)) between C(0) and AUCf and between AUCp and AUCf were examined. Median percentage prediction error (MPPE) and median absolute percentage prediction error (MAPE) were calculated. RESULTS: Correlation between C(0) and AUCf was 0.53. Using the 42 LSS equations, correlation between AUCp and AUCf ranged from 0.54 to 0.99. The MPPE and MAPE were <15% for 29 of 42 equations (62%), including five of eight equations based on sampling taken ≤2 h post-dose. Using the PK models in TCIWorks, AUCp derived from only C(0) values showed poor correlation with AUCf (r(2)=0.27-0.54) and unacceptable imprecision (MAPE 17.5-31.6%). In most cases, correlation, bias and imprecision estimates progressively improved with inclusion of a greater number of concentration time points. When concentration measurements at 0, 1, 2 and 4 h post-dose were applied, correlation between AUCp and AUCf ranged from 0.75 to 0.93, and MPPE and MAPE were <15% for all models examined. Using the Web-based consultancy service, correlation between AUCp and AUCf was 0.74, and MPPE and MAPE were 6.6 and 9.6%, respectively. CONCLUSIONS: Limited sampling methods better predict tacrolimus exposure compared with C(0) measurement. Several LSSs based on sampling taken 2 h or less post-dose predicted exposure with acceptable bias and imprecision. Generally, Bayesian forecasting methods required inclusion of a concentration measurement from >2 h post-dose to adequately predict exposure.

Rationale and design of the oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets trial for the correction of anaemia in peritoneal dialysis patients (HEMATOCRIT trial).

BACKGROUND: The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin ES) administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA)-treated peritoneal dialysis (PD) patients than conventional oral iron supplementation (Ferrogradumet). METHODS: Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp(R), Amgen) for >or= 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control) or HIP (1 tablet twice daily) for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements) will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA). Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin concentration), and occurrence of adverse events (especially gastrointestinal adverse events). DISCUSSION: This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry number ACTRN12609000432213.