A drug-drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5-lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam.

AIMS: Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre-clinical profiling suggests that time-dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co-administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time-/dose-dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity. METHODS: Open-label, fixed-sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2 mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug-drug interaction. RESULTS: Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co-administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co-administrations with two predicted therapeutically relevant doses of Atuliflapon. CONCLUSIONS: Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.

Immunological risk stratification and tailored minimisation of immunosuppression in renal transplant recipients.

BACKGROUND: The efficacy and safety of minimisation of immunosuppression including early steroid withdrawal in kidney transplant recipients treated with Basiliximab induction remains unclear. METHODS: This retrospective cohort study reports the outcomes from 298 consecutive renal transplants performed since 1st July 2010-June 2013 treated with Basiliximab induction and early steroid withdrawal in low immunological risk patients using a simple immunological risk stratification and 3-month protocol biopsy to optimise therapy. The cohort comprised 225 low-risk patients (first transplant or HLA antibody calculated reaction frequency (CRF ≤50% with no donor specific HLA antibodies) who underwent basiliximab induction, steroid withdrawal on day 7 and maintenance with tacrolimus and mycophenolate mofetil (MMF), and 73 high-risk patients who received tacrolimus, MMF and prednisolone for the first 3 months followed by long term maintenance immunosuppression with tacrolimus and prednisolone. High-risk patients not undergoing 3-month protocol biopsy were continued on triple immunosuppression. RESULTS: Steroid withdrawal could be safely achieved in low immunological risk recipients with IL2 receptor antibody induction. The incidence of biopsy-proven acute rejection was 15.1% in the low-risk and 13.9% in the high-risk group (including sub-clinical rejection detected at protocol biopsy). One- year graft survival was 93.3% and patient survival 98.5% in the low-risk group, and 97.3 and 100% respectively in the high-risk group. Graft function was similar in each group at 1 year (mean eGFR 61.2 ± 23.4 mL/min low-risk and 64.6 ± 19.2 mL/min high-risk). CONCLUSIONS: Immunosuppression regimen comprising basiliximab induction, tacrolimus, MMF and prednisolone with early steroid withdrawal in low risk patients and MMF withdrawal in high risk patients following a normal 3-month protocol biopsy is effective in limiting acute rejection episodes and produces excellent rates of patient survival, graft function and complications.

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report.

Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

Continuous Infusion of Low-Dose Iohexol Measures Changing Glomerular Filtration Rate in Critically Ill Patients.

OBJECTIVE: Measurement of changing glomerular filtration rate in acute kidney injury remains problematic. We have previously used a continuous infusion of low-dose Iohexol to measure glomerular filtration rate in stable subjects and postulate that changes greater than 10.3% in critically ill patients indicate acute kidney injury. Our objective is to explore the extent to which continuous infusion of low-dose Iohexol can be a measure of changing glomerular filtration rate during acute kidney injury. DESIGN: Clinical observational exploratory study. SETTING: Adult ICU. PATIENTS: Three patient groups were recruited: nephrectomy group: predictable onset of acute kidney injury and outcome (n = 10); surgery group: predictable onset of acute kidney injury, unpredictable outcome (n = 11); and acute kidney injury group: unpredictable onset of acute kidney injury and outcome (n = 13). INTERVENTIONS: Continuous infusion of low-dose Iohexol was administered for 24-80 hours. Plasma (ClP) and renal (ClR) Iohexol clearances were measured at timed intervals. MEASUREMENTS AND MAIN RESULTS: Kidney Disease: Improved Global Outcomes acute kidney injury criteria were fulfilled in 22 patients (nephrectomy = 5, surgery = 4, and acute kidney injury = 13); continuous infusion of low-dose Iohexol demonstrated acute kidney injury in 29 patients (nephrectomy = 10, surgery = 8, acute kidney injury = 11). Dynamic changes in glomerular filtration rate were tracked in all patients. In the nephrectomy group, ClR decreased by an expected 50% (50.8% ± 11.0%). Agreement between ClP and ClR improved with increasing duration of infusion: bias of ClP versus ClR at 48 hours was -0.1 ± 3.6 mL/min/1.73 m (limits of agreement: -7.2 to 7.1 mL/min/1.73 m). Coefficient of variation of laboratory sample analysis was 2.4%. CONCLUSIONS: Continuous infusion of low-dose Iohexol is accurate and precise when measuring glomerular filtration rate and tracks changes in patients with differing risks of acute kidney injury. Continuous infusion of low-dose Iohexol may provide a useful standard against which to test novel biomarkers for the diagnosis of acute kidney injury.

Validation of a continuous infusion of low dose Iohexol to measure glomerular filtration rate: randomised clinical trial.

INTRODUCTION: There is currently no accurate method of measuring glomerular filtration rate (GFR) during acute kidney injury (AKI). Knowledge of how much GFR varies in stable subjects is necessary before changes in GFR can be attributed to AKI. We have designed a method of continuous measurement of GFR intended as a research tool to time effects of AKI. The aims of this crossover trial were to establish accuracy and precision of a continuous infusion of low dose Iohexol (CILDI) and variation in GFR in stable volunteers over a range of estimated GFR (23-138 mL/min/1.73 m(2)). METHODS: We randomised 17 volunteers to GFR measurement by plasma clearance (PC) and renal clearance (RC) of either a single bolus of Iohexol (SBI; routine method), or of a continuous infusion of low dose Iohexol (CILDI; experimental method) at 0.5 mL/h for 12 h. GFR was measured by the alternative method after a washout period (4-28 days). Iohexol concentration was measured by high performance liquid chromatography/electrospray tandem mass spectrometry and time to steady state concentration (Css) determined. RESULTS: Mean PC was 76.7 ± 28.5 mL/min/1.73 m(2) (SBI), and 78.9 ± 28.6 mL/min/1.73 m(2) (CILDI), p = 0.82. No crossover effects occurred (p = 0.85). Correlation (r) between the methods was 0.98 (p < 0.0001). Bias was 2.2 mL/min/1.73 m(2) (limits of agreement -8.2 to 12.6 mL/min/1.73 m(2)) for CILDI. PC overestimated RC by 7.1 ± 7.3 mL/min/1.73 m(2). Mean intra-individual variation in GFR (CILDI) was 10.3% (p < 0.003). Mean ± SD Css was 172 ± 185 min. CONCLUSION: We hypothesise that changes in GFR >10.3% depict evolving AKI. If this were applicable to AKI, this is less than the 50% change in serum creatinine currently required to define AKI. CILDI is now ready for testing in patients with AKI. TRIAL REGISTRATION: This trial was registered with the European Union Clinical Trials Register ( https://www.clinicaltrialsregister.eu/ ), registration number: 2010-019933-89 .

Xenobiotic metabolism: the effect of acute kidney injury on non-renal drug clearance and hepatic drug metabolism.

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth.

Renohepatic crosstalk: does acute kidney injury cause liver dysfunction?

The concept of hepatorenal syndrome is well recognized, although incompletely understood. The converse clinical problem of hepatic dysfunction in patients with acute kidney injury (AKI) is less well recognized yet may be a contributor to the high patient morbidity and mortality seen in this group. This review draws together the available evidence for AKI's effect on the liver from animal models, pharmacological studies and recent clinical data. It examines liver function beyond clinically used blood tests, to determine the effect of AKI on hepatic synthetic function, acute phase response and drug metabolism. Parallels are drawn with other organ crosstalk in AKI and with liver-kidney interactions in chronic kidney disease. Definition of the pathophysiology of renohepatic crosstalk may lead to improved management strategies for this vulnerable patient group.

A published pharmacogenetic algorithm was poorly predictive of tacrolimus clearance in an independent cohort of renal transplant recipients.

AIMS: An algorithm based on the CYP3A5 genotype to predict tacrolimus clearance to inform the optimal initial dose was derived using data from the DeKAF study (Passey et al. Br J Clin Pharmacol 2011; 72: 948-57) but was not tested in an independent cohort of patients. Our aim was to test whether the DeKAF dosing algorithm could predict estimated tacrolimus clearance in renal transplant recipients at our centre. METHODS: Predicted tacrolimus clearance based on the DeKAF algorithm was compared with dose-normalized trough whole-blood concentrations (estimated clearance) on day 7 after transplantation in a single-centre cohort of 255 renal transplant recipients. RESULTS: There was a weak correlation (r = 0.431) between clearance based on dose-normalized trough whole-blood concentrations and DeKAF algorithm-predicted clearance. The means of the tacrolimus clearance predicted by the DeKAF algorithm and the estimated tacrolimus clearance based on the dose-normalized trough blood concentrations were plotted against the differences in the clearance as a Bland-Altman plot. Logarithmic transformation was performed owing to the increased difference in tacrolimus clearance as the mean clearance increased. There was a highly significant systematic error (P < 0.0005) characterized by a sloped regression line [gradient, 0.88 (95% confidence interval, 0.75-1.01)] on the Bland-Altman plot. CONCLUSIONS: The DeKAF algorithm was unable to predict the estimated tacrolimus clearance accurately based on real tacrolimus doses and blood concentrations in our cohort of patients. Other genes are known to influence the clearance of tacrolimus, and a polygenic algorithm may be more predictive than those based on a single genotype.

CYP3A5 genotype had no impact on intrapatient variability of tacrolimus clearance in renal transplant recipients.

BACKGROUND: The risk of long-term chronic allograft nephropathy and graft loss after kidney transplantation is increased in patients with a high intrapatient variability in the clearance of tacrolimus. CYP3A5 genotype has a significant influence on the oral bioavailability of tacrolimus and is a potential influence on variability of exposure. METHODS: The study population consisted of 118 renal transplant recipients with stable renal function 12 months after transplant. The intrapatient variability of tacrolimus concentration was calculated. The patients were divided into low- and high-intraindividual variability groups using the median variability of tacrolimus clearance as the cutoff value. RESULTS: No differences in baseline characteristics were observed between the expressers (n = 37) and nonexpressers (n = 81) except for ethnicity, which is in line with previous observations. Tacrolimus dose requirement was significantly higher in patients expressing CYP3A5, confirming earlier observations (P < 0.0001). However, intraindividual variability of tacrolimus clearance was not related to CYP3A5 genotype (P = 0.3331). CONCLUSIONS: The intrapatient variability of tacrolimus clearance was not associated with CYP3A5 genotype in stable renal transplant recipients.

UK Renal Registry 15th annual report: Chapter 3 demographic and biochemistry profile of kidney transplant recipients in the UK in 2011: national and centre-specific analyses.

INTRODUCTION: National transplant registries routinely focus on centre-specific patient and graft survival rates following renal transplantation. However other outcomes such as graft function (as measured by eGFR), haemoglobin and blood pressure are also important quality of care indicators. METHODS: Renal transplant activity, incident graft survival data and donor information were obtained from NHS Blood and Transplant. Laboratory and clinical variables and prevalent survival data were obtained from the UK Renal Registry. Data were analysed separately for prevalent and one year post-transplant patients. RESULTS: The only increase in transplant activity in 2011 was the use of donors after circulatory death. The death-censored graft failure rate was similar to previous years at 2.2% and the transplant patient death rates remained stable at 2.3 per 100 patient years. There was centre variation in outcomes including eGFR and haemoglobin in prevalent and 1 year post-transplant patients. Analysis of prevalent transplants by chronic kidney disease stage showed 13.6% with an eGFR <30 ml/min/1.73 m(2) and 1.7% with an eGFR <15 ml/min/1.73 m(2). Of those with CKD stage 5T, 34% had haemoglobin concentrations <10.0 g/dl, 19.8% phosphate concentrations ≥1.8 mmol/L and 7.1% adjusted calcium concentrations ≥2.6 mmol/L. Infection (23%), malignancy (21%), and cardiac disease (16%) remained amongst the commonest causes of death in patients with a functioning renal transplant. CONCLUSION: Significant variations in clinical outcomes (unadjusted for patient-specific variables) amongst kidney transplant recipients continued to exist in the UK and may reflect differences in healthcare delivery between renal centres.

UK Renal Registry 16th annual report: chapter 3 demographic and biochemistry profile of kidney transplant recipients in the UK in 2012: national and centre-specific analyses.

INTRODUCTION: National transplant registries routinely focus on centre-specific patient and graft survival rates following renal transplantation. However other outcomes such as graft function (as measured by eGFR), haemoglobin and blood pressure are also important quality of care indicators. METHODS: Renal transplant activity, incident graft survival data and donor information were obtained from NHS Blood and Transplant. Laboratory and clinical variables and prevalent survival data were obtained from the UK Renal Registry. Data were analysed separately for prevalent and one year post-transplant patients. RESULTS: The main increase in transplant activity in 2012 was the use of donors after circulatory death. The death-censored graft failure rate was similar to previous years at 2.2% and the transplant patient death rates remained stable at 2.3 per 100 patient years. There was centre variation in outcomes including eGFR and haemoglobin in prevalent and 1 year posttransplant patients. Analysis of prevalent transplants by chronic kidney disease stage showed 13.7% with an eGFR <30 ml/min/1.73 m(2) and 1.7% with an eGFR <15 ml/min/1.73 m(2). Of those with CKD stage 5T, 33% had haemoglobin concentrations <100 g/L, 27.6% phosphate concentrations 1.7 mmol/L and 20.5% adjusted calcium concentrations 2.5 mmol/L. Infection (23%) and malignancy (20%) remained amongst the commonest causes of death in patients with a functioning renal transplant. CONCLUSIONS: Significant variations in clinical outcomes (unadjusted for patient specific variables) amongst kidney transplant recipients continued to exist in the UK and may reflect differences in healthcare delivery between renal centres.

Chapter 3 Demographic and biochemistry profile of kidney transplant recipients in the UK in 2010: national and centre-specific analyses.

INTRODUCTION: National transplant registries routinely focus on centre-specific patient and graft survival rates following renal transplantation. However other outcomes such as graft function (as measured by eGFR), haemoglobin and blood pressure are also important quality of care indicators. METHODS: Renal transplant activity, incident graft survival data and donor information were obtained from NHS Blood and Transplant. Laboratory and clinical variables and prevalent survival data were obtained from the UK Renal Registry. Data were analysed separately for prevalent and one year post-transplant patients. RESULTS: The numbers of live and deceased kidney donors increased in 2010. The death-censored graft failure rate fell slightly to 2.4% and the transplant patient death rates remained stable at 2.5 per 100 patient years. There was centre variation in outcomes including eGFR and haemoglobin in prevalent and 1 year post-transplant patients. Analysis of prevalent transplants by chronic kidney disease stage showed 13.7% with an eGFR <30 ml/min/1.73 m(2) and 1.5% with an eGFR <15 ml/min/1.73 m(2). Of those with CKD stage 5 T, 36.1% had haemoglobin concentrations <10.5 g/dl, 22.9% phosphate concentrations ≥ 1.8 mmol/L and 6.2% adjusted calcium concentrations ≥ 2.6 mmol/L. Malignancy (23%) and infection (22%) remained the commonest two causes of death in prevalent transplant patients. CONCLUSION: Significant variations in clinical outcomes (unadjusted for patient-specific variables) amongst kidney transplant recipients continued to exist in the UK and may reflect differences in healthcare delivery between renal centres.

Limited sampling strategies for estimation of tacrolimus exposure in kidney transplant recipients receiving extended-release tacrolimus preparation.

Tacrolimus is the key component of most contemporary immunosuppressive drug regimens for the prevention of transplant rejection. Area under the concentration time curve over 24 h (AUC0-24 ) predicts efficacy, but predose (trough) tacrolimus blood concentration (C0 ) is currently used to guide dosing. In clinical or research situations where an estimate of AUC is required, collection of a full 24 h pharmacokinetic (PK) profile is cumbersome. Limited sampling strategies (LSSs) have been developed for some tacrolimus preparations but not for the new, extended-release, once-daily formulation of tacrolimus, ENVARSUS XR. Twenty-four kidney transplant recipients were enrolled in this study. Twenty-four tacrolimus PK profiles were obtained over 24 h. Multiple linear regression was used to generate LSSs with the best subset selection for accurate estimation of tacrolimus AUC0-24 . The predictive performance of each model was assessed in the evaluation group. The correlation between actual and predicted AUC0-24 was evaluated and mean percentage prediction error (MPE%), mean absolute percentage prediction error (MAE%), and root mean squared error (RMSE) were calculated for each prediction model to assess bias and precision. The selected LSSs were highly correlated to AUC0-24 compared with the correlation between C0 and AUC0-24 . Two and three sampling points limited sampling strategies: C0 , C2 , and C10 provide the most reliable and effective LSS for estimation of tacrolimus AUC0-24 in routine clinic use. These limited sampling models can be applied in therapeutic drug monitoring schemes to personalize tacrolimus dosing for kidney transplant recipients on treatment with extended-release tacrolimus.

Polymorphisms in CYP3A5, CYP3A4, and ABCB1 are not associated with cyclosporine pharmacokinetics nor with cyclosporine clinical end points after renal transplantation.

BACKGROUND: The association of CYP3A5, CYP3A4, and ABCB1 single nucleotide polymorphisms (SNPs) with cyclosporine (CsA) pharmacokinetics is controversial. The authors studied the influence of these SNPs on CsA pharmacokinetics as well as on the incidence of biopsy-proven acute rejection (BPAR) and renal function after kidney transplantation. METHOD: One hundred seventy-one patients participating in an international, randomized controlled trial were genotyped for CYP3A5*3, CYP3A4*1B and the ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T SNPs. The patients were treated with CsA, mycophenolate mofetil, and glucocorticoids. CsA was dosed to reach predose concentrations (C0) or two hours postdose concentrations (C2). Pharmacokinetic parameters were measured on Days 3 and 10 and Months 1, 3, 6, and 12 after transplantation. Renal function was assessed by measuring serum creatinine and calculating the creatinine clearance. The incidence of BPAR and delayed-graft function was recorded. RESULTS: CYP3A5, CYP3A4, and ABCB1 genotype were not associated with dose-adjusted CsA C0 or C2. The incidence of BPAR in this cohort was 16% and was comparable between the different ABCB1 genotype groups. No significant difference in the incidence of BPAR was found between CYP3A5 expressers (10%) and nonexpressers (18%) (P = 0.24) nor was there a difference in the incidence of BPAR between CYP3A4*1 homozygotes (5%) versus CYP3A4*1B carriers (18%) (P = 0.13). There were no differences with regard to creatinine clearance between the different CYP3A and ABCB1 genotype groups. CONCLUSION: According to the results, determination of CYP3A and ABCB1 SNPs pretransplantation is not helpful in determining the CsA starting dose and does not aid in predicting the risk of BPAR or worse renal function in an individual patient.

Design of FLAIR: a Phase 2b Study of the 5-Lipoxygenase Activating Protein Inhibitor AZD5718 in Patients With Proteinuric CKD.

INTRODUCTION: Patients with chronic kidney disease (CKD) remain at risk for kidney and cardiovascular events resulting from residual albuminuria, despite available treatments. Leukotrienes are proinflammatory and vasoconstrictive lipid mediators implicated in the etiology of chronic inflammatory diseases. AZD5718 is a potent, selective, and reversible 5-lipoxygenase activating protein (FLAP) inhibitor that suppresses leukotriene production. METHODS: FLAIR (FLAP Inhibition in Renal disease) is an ongoing phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of AZD5718 in patients with proteinuric CKD with or without type 2 diabetes. Participants receive AZD5718 at 3 different doses or placebo once daily for 12 weeks, followed by an 8-week extension in which they also receive dapagliflozin (10 mg/d) as anticipated future standard of care. The planned sample size is 632 participants, providing 91% power to detect 30% reduction in urinary albumin-to-creatinine ratio (UACR) between the maximum dose of AZD5718 and placebo. The dose-response effect of AZD5718 on UACR after the dapagliflozin extension is the primary efficacy objective. Key secondary objectives are the dose-response effect of AZD5718 plus current standard of care on UACR and acute effects of treatment on the estimated glomerular filtration rate. Safety, tolerability, AZD5718 pharmacokinetics, and analyses of biomarkers that may predict or reflect response to AZD5718 are additional objectives. CONCLUSION: FLAIR will provide data on the effects of 5-lipoxygenase pathway inhibition in patients with proteinuric CKD with or without type 2 diabetes, and will form the basis for future clinical trials (ClinicalTrials.gov: NCT04492722).

Black renal transplant recipients have poorer long-term graft survival than CYP3A5 expressers from other ethnic groups.

BACKGROUND: African American transplant recipients have poorer long-term outcomes than Caucasian Americans. This difference was not found in French patients, suggesting socialized medicine overcame this disparity. It has also been hypothesized that the difference relates to the higher prevalence of Black individuals who express the metabolic enzyme cytochrome P4503A5 (CYP3A5), with consequent altered handling of immunosuppressive drugs. METHODS: Records of 555 (50 Black; 505 non-Black) sequential renal transplant recipients from a single UK centre were analysed. RESULTS: Outcomes were significantly worse for Black patients: death-censored graft survival (5-year 66% versus 87%, P = 0.001); halving of year one estimated glomerular filtration rate (mean 8.8 versus 10.8 years, P = 0.008); first-year graft loss (12% versus 3.8%, P = 0.02); and death-censored graft survival in patients surviving the first year with functioning grafts (5-year 77% versus 94%, P = 0.02). Death-censored 5-year graft survival was poorer in Black CYP3A5 expressers than in non-Black CYP3A5 expressers (62% versus 93%, P = 0.002). Following multivariate analysis, the Black group demonstrated poorer graft survival as compared to the non-Black group (hazard ratio 0.46, 95% CI 0.25-0.85, P = 0.002). In a subgroup of genotyped transplant recipients, ethnicity (hazard ratio 0.31, 95% CI 0.15-0.64, P = 0.002), and not CYP3A5 expresser status, persists as an independent risk factor for graft survival following multivariate analysis. CONCLUSION: In this cohort of patients with socialized medicine, Black recipients had poorer long-term outcomes than individuals from other ethnic groups. This was independent of CYP3A5 expresser status.

Use of pharmacogenetics to optimize immunosuppressive therapy.

Pharmacogenetic strategies offer promise as an adjunct to therapeutic drug monitoring in achieving target blood concentrations of the immunosuppressive drugs as early as possible after transplantation. To date, the only strategy to have been tested in a clinical trial is the use of the cytochrome P450 3A5 (CYP3A5) genotype to predict tacrolimus dose. Other potential candidates are CYP3A5 and sirolimus and UGT1A9 for mycophenolate. There are also genetic predictors of pharmacodynamics, including IMPDH1 for mycophenolate and ABCB1 for cyclosporine that may identify individuals at particular risk of efficacy failure or toxicity with a given drug. As pharmacogenetic testing moves into routine clinical practice, standards for service delivery and reporting of results need to be established.

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy.

BACKGROUND: Kidney transplant recipients (KTRs) with "operational tolerance" (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. METHODS: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. FINDINGS: IS drugs explained up to 50% of the variability in gene-expression and 20-30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4-1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88-0⋅94) in cross-validation and 0⋅97 (0⋅93-1⋅00) in six months follow-up samples. INTERPRETATION: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial. FUNDING: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas' Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007-2013 [HEALTH-F5-2010-260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19-06-00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].