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This article summarizes the lessons learned from the COCKTAIL study: an open, three‐armed, single‐center study including patients with obesity scheduled for treatment with Roux‐en‐Y gastric bypass (RYGB) or nonsurgical calorie restriction, and a normal‐ to overweight control group. The clinical implications of the results from multiple peer‐reviewed articles describing the effects of RYGB, severe caloric restriction, weight loss, and type 2 diabetes on the in vivo activity and protein expression of drug‐metabolizing enzymes (cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 3A) and transporters (DMETs; organic anion‐transporting polypeptide (OATP) 1B1 and P‐glycoprotein (P‐gp)) are discussed in the perspective of three clinically relevant questions: (1) How should clinicians get the dose right in patients after RYGB? (2) Will drug disposition in patients with obesity be normalized after successful weight loss? (3) Are dose adjustments needed according to obesity and diabetes status? Overall, RYGB seems to have a lower impact on drug disposition than previously assumed, but clinicians should pay close attention to drugs with a narrow therapeutic range or where a high maximum drug concentration may be problematic. Whether obesity‐related alterations of DMETs normalize with substantial weight loss depends on the DMET in question. Obesity and diabetes downregulate the in vivo activity of CYP2C19 and CYP3A (only obesity) but whether substrate drugs should be dose adjusted is also dependent on other factors that influence clearance, that is, liver blood flow and protein binding. Finally, we recommend frequent and individualized follow‐up due to high inter‐ and intraindividual variability in these patients, particularly following RYGB. [ABSTRACT FROM AUTHOR]

Aims: Finger‐prick sampling has emerged as an attractive tool for therapeutic drug monitoring and associated diagnostics. We aimed to validate the clinical performance of using two volumetric devices (Capitainer® qDBS and Mitra®) for monitoring tacrolimus, creatinine and haemoglobin in kidney transplant (KTx) recipients. Secondarily, we evaluated potential differences between finger‐prick sampling performed by healthcare professionals vs. self‐sampling, and differences between the two devices. Methods: We compared finger‐prick and venous sampling in three settings: microsampling performed by healthcare personnel, self‐sampling under supervision, unsupervised self‐sampling. The finger‐prick samples were analysed with adapted methods and results compared to routine method analysis of the venous blood samples. Results: Twenty‐five KTx recipients completed the main study and 12 KTx recipients completed a post hoc validation study. For tacrolimus measurements and predicted area under the curve, the proportions within ±20% difference were 79%–96% for Capitainer and 77%–95% for Mitra. For creatinine and haemoglobin, the proportions within ±15% were 92%–100% and 93%–100% for Capitainer and 79%–96% and 67%–92% for Mitra, respectively. Comparing sampling situations, the success rate was consistent for Capitainer (92%–96%), whereas Mitra showed 72%–88% and 52%–72% success rates with samples collected by healthcare personnel and the patients themselves. Conclusions: Capitainer and Mitra are technically feasible for measuring tacrolimus, creatinine and haemoglobin. In the context of self‐sampling, Capitainer maintained consistent sampling success and analytical quality. Implementing volumetric finger‐prick self‐sampling for the monitoring of tacrolimus, creatinine and haemoglobin may simplify and improve the follow‐up of KTx recipients. [ABSTRACT FROM AUTHOR]

Background: Reliable methods to detect and reduce medication nonadherence in solid organ‐transplanted (SOT) adolescents are warranted. We aimed to evaluate the feasibility of combining a medication‐manager application (TusenTac®‐app) with home‐sampling of tacrolimus (Tac) in young SOT recipients. Methods: Kidney and combined SOT recipients between 14 and 25 years were included. During an 8‐week intervention period, the participants were instructed to use the transplant‐specific, age‐adapted TusenTac®‐app daily and to perform weekly at‐home Tac trough finger‐prick microsampling. Microsample Tac concentrations were controlled against timed venous samples twice. Medication implementation and persistence adherence were measured with BAASIS© questionnaires, TusenTac®‐registrations, Tac trough concentration coefficient of variation (CV%) and self‐reporting by interview. For comparison, venous Tac trough CV% were obtained from the year before and after the short‐term intervention. Results: Twenty‐two recipients were included, two withdrawals, leaving 20; median age 17.9 (14.5–24.8) years, 12 females (60%). The participants registered their dosage intake 88% (1502/1703) of the expected times, and 90% (106/118) of the microsamples were obtained correctly. At inclusion, 11 recipients (55%) were nonadherent assessed with BAASIS© questionnaire, four of these (36%) turned adherent during the intervention period. At the end, 70% reported improved timing‐adherence at the interview. There was no significant change in TacCV% from the year before to the year after the short‐term intervention. Home‐sampling was reliable and measured Tac concentrations accurately. Conclusions: Home‐monitoring, combining Tac finger‐prick microsampling and a medication‐manager app, is feasible in adolescent SOT recipients with 70% perceived improvement in medication timing‐adherence. There were no significant long‐term changes in TacCV% confirming the need for continuous use and individualized interventions. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether mesna—sodium‐2‐mercaptoethane sulfonate) can reduce diet‐induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. Methods: C3H/HeH mice were shifted to a high‐fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24‐hour urine. Results: Compared with controls, mesna‐treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; Poverall =.002), but similar lean mass gain. In men with overweight, mesna doses of 400‐1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post‐dosing). With increasing mesna dose, tCys AUC0‐12h decreased (Ptrend <.001), and urine tCys excretion increased (Ptrend =.004). Conclusions: Mesna reduces diet‐induced fat gain in mice. In men with overweight, single oral doses of mesna (800‐1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys‐lowering by repeated mesna administration on weight loss in humans deserves investigation. [ABSTRACT FROM AUTHOR]

Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross‐sectional analysis; 29 with T2DM and obesity (T2DM‐obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (−0.39 [95% CI: −0.82, −0.09]) and 40% (−0.09 fmol/μg protein [95% CI: −0.18, −0.003]) lower in T2DM‐obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform‐specific. [ABSTRACT FROM AUTHOR]

Aim: Roux‐en‐Y gastric bypass (RYGB) may influence drug disposition due to surgery‐induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short‐ and long‐term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5‐hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross‐sectionally compare these CYP‐activities with normal‐to‐overweight controls. Methods: This trial included patients with severe obesity preparing for RYGB (n = 40) or diet‐induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3‐week low‐energy diet (<1200 kcal/day, weeks 0‐3) followed by a 6‐week very‐low‐energy diet or RYGB (both <800 kcal/day, weeks 3‐9). Follow‐up time was 2 years, with four pharmacokinetic investigations. Results: Mean ± SD weight loss from baseline was similar in the RYGB‐group (13 ± 2.4%) and the diet group (10.5 ± 3.9%) at week 9, but differed at year 2 (RYGB −30 ± 6.9%, diet −3.1 ± 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3‐9), but not in the diet‐group (between‐group difference −0.30 [−0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7‐fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. Conclusion: Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed. [ABSTRACT FROM AUTHOR]

Aims: Iohexol clearance has been proposed to estimate the glomerular filtration rate (GFR). A population pharmacokinetics (popPK) model was developed from heterogeneous patients. A Bayesian estimator (MAP‐BE) based on a limited sampling strategy (LSS) was derived and evaluated in external patients. Methods: Full pharmacokinetic data (7–12 samples) from 172 patients receiving iohexol for measurement of their GFR (unstable and stable ICU patients, liver failure patients and kidney transplant patients) were split into development (n = 136) and validation (n = 36) datasets. A PopPK model was developed in Monolix and was used to develop MAP‐BE based on LSS. Its performance for GFR estimation was evaluated in the validation set. Results: A two‐compartment model with first‐order elimination best described the data. The final model included the type of patients on volume of distribution (Vd), clearance and intercompartmental constants, serum creatinine on clearance and body weight on Vd. The best LSS included samples at 0.1–1‐9 h exhibiting a relative mean prediction error (MPE) (RMSE) = −3.7% (14.3%) and better performance than the Bröchner‐Mortensen formula (−3.0%/17%). Split by type of patients, the highest interindividual variability and imprecision was observed in unstable ICU patients (MPE (RMSE) = 3.7% (18.8%)) while the best performances were obtained for renal transplant patients (MPE (RMSE) = 1.0% (5.8%)). All LSS that included samples before 9 hours for the third sample were associated with an increased imprecision. Conclusion: A single MAP‐BE of iohexol based on a three‐sample LSS for four heterogeneous populations was developed and allowed accurate estimation of GFR in kidney transplant patients, slightly biased in stable ICU patients and slightly imprecise in unstable ICU patients. [ABSTRACT FROM AUTHOR]

Mathematical models, such as physiologically‐based pharmacokinetic models, are used to predict, for example, drug disposition and toxicity. However, populations differ in the abundance of proteins involved in these processes. To improve the building and refinement of such models, they must take into account these interindividual variabilities. In this study, we used global proteomics to characterize the protein composition of jejunum and liver from 37 donors with obesity enrolled in the COCKTAIL study. Liver protein levels from the 37 donors were further compared with those from donors without obesity. We quantified thousands of proteins and could present the expression of several drug‐metabolizing enzymes, for the first time, in jejunum, many of which belong to the cytochrome P450 (CYP) (e.g., CYP2U1) and the amine oxidase (flavin‐containing) (e.g., monoamine oxidase A (MAOA)) families. Although we show that many metabolizing enzymes had greater expression in liver, others had higher expression in jejunum (such as, MAOA and CES2), indicating the role of the small intestine in extrahepatic drug metabolism. We further show that proteins involved in drug disposition are not correlated in the two donor‐matched tissues. These proteins also do not correlate with physiological factors such as body mass index, age, and inflammation status in either tissue. Furthermore, the majority of these proteins are not differently expressed in donors with or without obesity. Nonetheless, interindividual differences were considerable, with implications for personalized prediction models and systems pharmacology. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the potential clinical relevance of estimating the apparent clearance (CL/F) of atorvastatin through population pharmacokinetic (PopPK) modeling with samples collected in a real‐life setting in a cohort of ambulatory patients at risk of cardiovascular disease by using an opportunistic sampling strategy easily accessible in clinical routine. A total of 132 pharmacokinetic (PK) samples at a maximum of three visits were collected in the 70 included patients. The effects of demographic, genetic, and clinical covariates were also considered. With the collected data, we developed a two‐compartment PopPK model that allowed estimating atorvastatin CL/F relatively precisely and considering the genotype of the patient for SLCO1B1 c.521T>C single‐nucleotide polymorphism (SNP). Our results indicate that the estimation of the CL/F of atorvastatin through our PopPK model might help in identifying patients at risk of myalgia. Indeed, we showed that a patient presenting a CL/F lower than 414.67 L h−1 is at risk of suffering from muscle discomfort. We also observed that the CL/F was correlated with the efficacy outcomes, suggesting that a higher CL/F is associated with a better drug efficacy (i.e., a greater decrease in total and LDL‐cholesterol levels). In conclusion, our study demonstrates that PopPK modeling can be useful in daily clinics to estimate a patient' atorvastatin clearance. Notifying the clinician with this information can help in identifying patients at risk of myalgia and gives indication about the potential responsiveness to atorvastatin therapy. [ABSTRACT FROM AUTHOR]

It remains uncertain whether pharmacokinetic changes following Roux‐en‐Y gastric bypass (RYGB) can be attributed to surgery‐induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short‐ and long‐term effects of RYGB and calorie restriction on CYP3A‐activity, and cross‐sectionally compare CYP3A‐activity with normal weight to overweight controls using midazolam as probe drug. This three‐armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet‐induced (n = 41) weight‐loss, and controls (n = 18). Both weight‐loss groups underwent a 3‐week low‐energy‐diet (<1200 kcal/day) followed by a 6‐week very‐low‐energy‐diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight‐loss at week 9 (13 ± 2.4% vs. 11 ± 3.6%), but differed substantially after 2 years (−30 ± 7.0% vs. −3.1 ± 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 ± 7.5% in the RYGB group and 32 ± 6.1% in the diet group at year 2 compared with baseline, with no between‐group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A‐activity is not only dependent on weight‐loss through RYGB. [ABSTRACT FROM AUTHOR]

Rosuvastatin is a frequently used probe to study transporter‐mediated hepatic uptake. Pharmacokinetic models have therefore been developed to predict transporter impact on rosuvastatin disposition in vivo. However, the interindividual differences in transporter concentrations were not considered in these models, and the predicted transporter impact was compared with historical in vivo data. In this study, we investigated the influence of interindividual transporter concentrations on the hepatic uptake clearance of rosuvastatin in 54 patients covering a wide range of body weight. The 54 patients were given an oral dose of rosuvastatin the day before undergoing gastric bypass or cholecystectomy, and pharmacokinetic (PK) parameters were established from each patient's individual time‐concentration profiles. Liver biopsies were sampled from each patient and their individual hepatic transporter concentrations were quantified. We combined the transporter concentrations with in vitro uptake kinetics determined in HEK293‐transfected cells, and developed a semimechanistic model with a bottom‐up approach to predict the plasma concentration profiles of the single dose of rosuvastatin in each patient. The predicted PK parameters were evaluated against the measured in vivo plasma PKs from the same 54 patients. The developed model predicted the rosuvastatin PKs within two‐fold error for rosuvastatin area under the plasma concentration versus time curve (AUC; 78% of the patients; average fold error (AFE): 0.96), peak plasma concentration (Cmax; 76%; AFE: 1.05), and terminal half‐life (t1/2; 98%; AFE: 0.89), and captured differences in the rosuvastatin PKs in patients with the OATP1B1 521T

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC‐guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice‐daily tacrolimus in a real‐life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting‐state and under real‐life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting‐conditions: 45% higher peak‐concentration and 20% higher AUC following the morning dose. In the real‐life nonfasting setting, the PK‐profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting‐state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real‐life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting‐state, whereas flatter PK‐profiles and no circadian variation was present in a real‐life, nonfasting setting. [ABSTRACT FROM AUTHOR]

Drug dosing is challenging in patients with end‐stage renal disease. Not only is renal drug elimination reduced, but nonrenal clearance pathways are also altered. Increasing evidence suggest that uremia impacts drug metabolizing enzymes and transporters leading to changes in nonrenal clearance. However, the exact mechanisms are not yet fully understood, and the acute effects of dialysis are inadequately investigated. We prospectively phenotyped cytochrome P450 3A (CYP3A; midazolam) and P‐glycoprotein (P‐gp)/organic anion‐transporting proteins (OATP; fexofenadine) in 12 patients on chronic intermittent hemodialysis; a day after ("clean") and a day prior to ("dirty") dialysis. Unbound midazolam clearance decreased with time after dialysis; median (range) reduction of 14% (−3% to 41%) from "clean" to "dirty" day (P = 0.001). Fexofenadine clearance was not affected by time after dialysis (P = 0.68). In conclusion, changes in uremic milieu between dialysis sessions induce a small, direct inhibitory effect on CYP3A activity, but do not alter P‐gp/OATP activity. [ABSTRACT FROM AUTHOR]

Living donors (LDs) are preferred over DDs for renal transplantation in children due to superior GS. Oslo University Hospital has never restricted living donation by upper age. The aim of this study was to investigate long‐term outcomes using grandparents (GPLD) compared to PLD. Retrospective nationwide review in the period 1970‐2017. First renal graft recipients using a GPLD were compared to PLD kidney recipients for long‐term renal function and GS. 278 children (≤18 years) received a first renal transplant: 27/251 recipients with a GPLD/PLD. GPLD (median 59 (42‐74) years) were significantly older than PLD (median 41 (23‐65) years, (P <.001). Median DRAD was 52 (38‐70) vs 28 (17‐48) years, respectively. GS from GPLD and PLD had a 1‐, 5‐, and 10‐year survival of 100%, 100%, and 90% vs 93%, 82%, and 72%, respectively (P =.6). In a multivariate Cox regression analysis adjusted for gender, donor age, recipient age, and year of transplant, this finding was similar (HR 0.98; 95% CI 0.34‐2.84, P =.97). Five‐year eGFR was 47.3 and 59.5 mL/min/1.73 m2 in the GPLD and PLD groups (P =.028), respectively. In this nationwide retrospective analysis, GS for pediatric renal recipients using GPLD was comparable to PLD. Renal function assessed as eGFR was lower in the GPLD group. The GPLD group was significantly older than the PLD group, but overall this did not impact transplant outcome. Based on these findings, older age alone should not exclude grandparent donations. [ABSTRACT FROM AUTHOR]

Background: Patients with diabetes mellitus treated with successful pancreas transplantation (PTX) normalize hyperglycemia, but are exposed to immunosuppressive drugs that may impair endothelial function. This study aimed to evaluate endothelial function in single PTX recipients. Methods: Flow‐mediated dilatation (FMD) in the brachial artery was measured by ultrasound 8 weeks after transplantation in single PTX (n = 27) and compared with healthy controls (n = 58), simultaneous pancreas and kidney recipients (n = 9), and kidney transplant recipients with (n = 41) and without (n = 95) diabetes mellitus. Adjustments for age, gender, blood pressure, and body mass index were included in a linear regression model. Changes in FMD from before to 1 year after transplantation were assessed in a subgroup of PTX recipients (n = 9). Results: Flow‐mediated dilatation% in PTX recipients was not inferior to healthy controls (8.7 ± 3.6 vs 7.7 ± 3.3, P =.06) and simultaneous pancreas and kidney recipients (6.7 ± 4.5, P =.24) in an adjusted model, and superior to kidney recipients with and without diabetes (3.0 ± 3.0 and 4.8 ± 3.3, respectively, both P <.005). FMD% improved significantly from eight weeks to one year after PTX, mean 7.9 ± 4.2% vs 11.8 ± 4.8% (N = 9; P =.03). Conclusion: Flow‐mediated dilatation is well preserved in patients undergoing pancreas transplantation and is not impaired when immunosuppressive drugs are introduced. [ABSTRACT FROM AUTHOR]

Summary: Anatomical changes in the gastrointestinal tract and subsequent weight loss may influence drug disposition and thus drug dosing following bariatric surgery. This review systematically examines the effects of bariatric surgery on drug pharmacokinetics, focusing especially on the mechanisms involved in restricting oral bioavailability. Studies with a longitudinal before‐after design investigating the pharmacokinetics of at least one drug were reviewed. The need for dose adjustment following bariatric surgery was examined, as well as the potential for extrapolation to other drugs subjected to coinciding pharmacokinetic mechanisms. A total of 22 original articles and 32 different drugs were assessed. The majority of available data is based on Roux‐en‐Y gastric bypass (RYGBP) (18 of 22 studies), and hence, the overall interpretation is more or less limited to RYGBP. In the case of the majority of studied drugs, an increased absorption rate was observed early after RYGBP. The effect on systemic exposure allows for a low degree of extrapolation, including between drugs subjected to the same major metabolic and transporter pathways. On the basis of current understanding, predicting the pharmacokinetic change for a specific drug following RYGBP is challenging. Close monitoring of each individual drug is therefore recommended in the early postsurgical phase. Future studies should focus on the long‐term effects of bariatric surgery on drug disposition, and they should also aim to disentangle the effects of the surgery itself and the subsequent weight loss. [ABSTRACT FROM AUTHOR]

Background and aims: Intranasal (i.n.) naloxone is an established treatment for opioid overdose. Anyone likely to witness an overdose should have access to the antidote. We aimed to determine whether an i.n. formulation delivering 1.4 mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8 mg intramuscular (i.m.) naloxone. Design Open, randomized four‐way cross‐over trial. Setting: Clinical Trials Units in St Olav's Hospital, Trondheim and Rikshospitalet, Oslo, Norway. Participants: Twenty‐two healthy human volunteers, 10 women, median age = 25.8 years. Intervention and comparator: One and two doses of i.n. 1.4 mg naloxone compared with i.m. 0.8 mg and intravenous (i.v.) 0.4 mg naloxone. Measurements Quantification of plasma naloxone was performed by liquid chromatography tandem mass spectrometry. Pharmacokinetic non‐compartment analyses were used for the main analyses. A non‐parametric pharmacokinetic population model was developed for Monte Carlo simulations of different dosing scenarios. Findings Area under the curve from administration to last measured concentration (AUC0‐last) for i.n. 1.4 mg and i.m. 0.8 mg were 2.62 ± 0.94 and 3.09 ± 0.64 h × ng/ml, respectively (P = 0.33). Maximum concentration (Cmax) was 2.36 ± 0.68 ng/ml for i.n. 1.4 mg and 3.73 ± 3.34 for i.m. 0.8 mg (P = 0.72). Two i.n. doses showed dose linearity and achieved a Cmax of 4.18 ± 1.53 ng/ml. Tmax was reached after 20.2 ± 9.4 minutes for i.n. 1.4 mg and 13.6 ± 15.4 minutes for i.m. 0.8 mg (P = 0.098). The absolute bioavailability for i.n. 1.4 mg was 0.49 (±0.24), while the relative i.n./i.m. bioavailability was 0.52 (±0.25). Conclusion: Intranasal 1.4 mg naloxone provides adequate systemic concentrations to treat opioid overdose compared with intramuscular 0.8 mg, without statistical difference on maximum plasma concentration, time to maximum plasma concentration or area under the curve. Simulations support its appropriateness both as peer administered antidote and for titration of treatment by professionals. [ABSTRACT FROM AUTHOR]

Abstract: This study estimates the effects on peak oxygen uptake (VO2 peak), QoL, and mental health after the introduction of an adjusted post‐transplant follow‐up program, that is, early physiotherapy and focus on the importance of physical activity. VO2 peak was measured by a treadmill exercise test in 20 renal‐transplanted children on the adjusted post‐transplant follow‐up and compared with a group of 22 patients investigated in a previously, before the implementation of our new follow‐up routines. PedsQL and The Strengths and Difficulties Questionnaire (SDQ) were used to assess QoL and mental health in 45 patients on the new as compared to 32 patients on the previous follow‐up strategy. The patients exposed to early physiotherapy and a higher focus on physical activity had significantly higher VO2 peak (44.3 vs 33.5 mL kg−1 min−1, P = .031) in addition to improved QoL (P = .003) and mental health scores (P = .012). The cardiovascular risk profile was similar in both groups aside from significantly higher triglycerides in the present cohort. Small efforts as early physiotherapy and increased focus on physical activity after pediatric renal transplantation have significant impact on cardiorespiratory fitness, QoL, and mental health. The importance of physical activity should therefore be emphasized in follow‐up programs. [ABSTRACT FROM AUTHOR]

Abstract: Arterial stiffness, visceral fat, and hyperglycemia are acknowledged risk factors for adverse outcomes after transplantation, but whether arterial stiffness is associated with visceral adipose tissue and hyperglycemia is unknown. We studied 162 non‐diabetic kidney transplant recipients 8‐10 weeks after transplantation. Arterial stiffness was measured as pulse wave velocity (PWV) by SphygmoCor and visceral fat using a validated software applied on DXA scans. Also a standard oral glucose tolerance test was performed. Median PWV was 8.6 m/s (IQR 7.3‐10.4 m/s). Patients in the upper quartile of PWV had 31%‐106% higher visceral fat percentage (P < 0.001), they were older (P < 0.001) and had a fasting plasma glucose of 5.8 mmol/L that was higher than in the other quartiles (P = 0.006). In univariate analysis, visceral fat percentage and age were the parameters strongest associated with PWV (P < 0.001), but cholesterol and glucose were also significant (P < 0.05). In multivariate analysis, visceral fat was the only significant predictor of PWV along with age (P < 0.001). In conclusion, arterial stiffness is significantly associated with visceral fat but not hyperglycemia in non‐diabetic kidney transplant patients. We identified age and VAT as risk variables for arterial stiffness. A potential reversibility of arterial wall stiffness with reduction in VAT needs further study. [ABSTRACT FROM AUTHOR]

Abstract: Kidney allograft inflammation is associated with proinflammatory modifications of peripheral blood mononuclear cells, suggesting that renal inflammation contributes to systemic inflammation. Thus, the aim of this study was to evaluate the relationship between subclinical inflammation in surveillance biopsies performed at 1 year and systemic inflammation assessed by C‐reactive protein (CRP) levels at the time of biopsy. We analyzed 544 surveillance biopsies performed at 1 year that were classified as normal (n = 368), borderline (n = 148), or subclinical rejection (SCR) (n = 28). CRP levels were divided into quartiles. Patients in 1st, 2nd, and 3rd quartile were classified as low CRP (n = 408) and patients in the 4th quartile as high CRP (n = 136). Univariate analysis showed that the proportion of patients with SCR was higher in the high CRP group (10.3% vs 3.4%, P = 0.0067). Multivariate analysis showed that independent predictors of high CRP were body mass index (odds ratio [OR] 1.072 and 95% confidence interval [CI] 1.027‐1.119), a positive urine culture at the day of the biopsy (OR 2.760 and 95% CI 1.205‐6.323), and the presence of SCR at 1‐year surveillance biopsy (OR 7.260 and 95% CI 3.530‐14.935). In summary, we describe that subclinical acute rejection constitutes an independent predictor of systemic inflammation as measured by CRP. [ABSTRACT FROM AUTHOR]

A serum test called T50 assesses the overall propensity for calcification of the blood and is associated with cardiovascular outcomes. We aimed to examine T50 over time in kidney transplant recipients and also address any effects of ibandronate. Serum samples taken from kidney transplant patients included in a prospective, randomized placebo controlled study of ibandronate were analyzed in retrospect. Adequate analyses were performed at baseline (approximately 3 weeks after transplantation) in 129 patients, at 10 weeks in 127 patients and at 1 year in 123 patients. There were no statistical differences between ibandronate and placebo treatment in terms of T50 at 10 weeks ( P = .094) or at 1 year ( P = .116). Baseline T50 was a significant covariate ( P < .0001) for T50 scores at 10 weeks and 1 year. In the total cohort, there was a highly significant ( P < .0001) increase in T50 of 26.6% after 10 weeks and T50 remained stable after 1 year. T50 change was inversely correlated to phosphate of −0.515 ( P < .0001) and to change in serum albumin ( P < .03). We found that T50 increased from baseline to 10 weeks after transplantation with no further change after 1 year. Ibandronate had no effect on T50. [ABSTRACT FROM AUTHOR]

However, obtaining a renal transplant biopsy may be challenging in patients treated with anticoagulation therapy. In our experience, percutaneous biopsy of renal grafts with anticoagulation is safe when withdrawing DOAC 2 days, and warfarin 5 days, prior to biopsy. DEAR EDITOR Renal transplantation is the preferred renal replacement therapy for most patients with end stage kidney failure. [Extracted from the article]

Aims Tacrolimus is a cornerstone in modern immunosuppressive therapy after kidney transplantation. Tacrolimus dosing is challenged by considerable pharmacokinetic variability, both between patients and over time after transplantation, partly due to variability in cytochrome P450 3A (CYP3A) activity. The aim of this study was to assess the value of the endogenous CYP3A marker 4β-hydroxycholesterol (4βOHC) for tacrolimus dose individualization early after kidney transplantation. Methods Data were obtained from 79 adult kidney transplant recipients who contributed a total of 625 4βOHC measurements and 1999 tacrolimus whole blood concentrations during the first 2 months after transplantation. The relationships between 4βOHC levels and individual estimates of tacrolimus apparent plasma clearance (CL/Fplasma) at different time points after transplantation were investigated using scatterplots and population pharmacokinetic modelling. Results There was no significant correlation between pre-transplant 4βOHC levels and tacrolimus CL/Fplasma the first week ( r = 0.19 [95% CI −0.03-0.40]) or between 4βOHC and tacrolimus CL/Fplasma 1 week ( r = 0.20 [−0.11-0.47]), 4 weeks ( r = 0.21 [−0.07-0.46]) or 2 months ( r = 0.24 [−0.03-0.48]) after transplantation ( P ≥ 0.06). In the population analysis, time-varying 4βOHC was not a statistically significant covariate on tacrolimus CL/Fplasma, neither in terms of absolute values ( P = 0.11) nor in terms of changes from baseline ( P = 0.17). 4βOHC values increased between 1 week and 2 months after transplantation (median change +57% [IQR +22-83%], P < 0.001), indicating increasing CYP3A activity. Contradictorily, tacrolimus CL/Fplasma decreased over the same period (median change −13% [IQR −3 to −26%], P < 0.001). Conclusions 4βOHC does not appear to have a clinical potential to improve individualization of tacrolimus doses early after kidney transplantation. [ABSTRACT FROM AUTHOR]

Background Chronic widespread musculoskeletal complaints (CWMSC) are a prevalent condition with a large impact on quality of life and with a large burden on society. Studies investigating the relationship between CWMSC and mortality have yielded inconsistent results. The present study aimed to clarify this relationship through a systematic review of the existing literature, including meta-analyses, to estimate pooled results and heterogeneity. Methods The MEDLINE, EMBASE and Science Citation Index Expanded databases were searched in February 2016. Broad search terms were used to identify as many observational studies as possible that investigated the association between CWMSC and mortality. The identified studies were evaluated according to predetermined inclusion criteria. Results Six studies fulfilled the inclusion criteria. In pooled unadjusted analyses of three studies evaluating CWMSC, a non-significant tendency of increased overall mortality was found [mortality risk ratio (MRR) 1.69, 95% confidence interval (CI) 0.91-3.14]. However, in pooled analyses of all six studies reporting adjusted results, the non-significant tendency for higher mortality rates in those with CWMSC was nearly eliminated (MRR 1.13, 95% CI 0.95-1.34). Heterogeneity between studies was moderate to high, particularly regarding the use of confounding factors. Conclusions In this systematic review, based on a limited number of studies, pooled data gave no evidence of a higher mortality rate among individuals with CWMSC. The non-significant tendency for a higher mortality rate in unadjusted pooled analyses was nearly eliminated in the adjusted pooled analyses, considering lifestyle factors such as physical activity smoking. In population-based studies evaluating the relationship between CWMSC and mortality rates, we recommend that both unadjusted and adjusted analyses should be presented. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Body composition after kidney transplantation is linked to glucose metabolism, and impaired glucose metabolism is associated with increased risk of cardiovascular events and death. One year after transplantation, we examined 150 patients for post-transplant diabetes performing oral glucose tolerance tests and body composition measurements including visceral adipose tissue ( VAT) content from dual-energy X-ray absorptiometry scans. We found that glucose metabolism was generally improved over the first year post-transplant, and that the levels of VAT and percentage VAT of total body fat mass ( VAT%tot BFM) were lowest in those with normal glucose tolerance and highest in those with post-transplant diabetes mellitus. In a multivariable linear regression analysis, 87.4% of the variability in fasting glucose concentration was explained by insulin resistance ( P<.001, HOMA- IR index), beta cell function ( P<.001, HOMA-beta), VAT%tot BFM ( P=.007), and body mass index ( BMI; P=.015; total model P<.001), while insulin resistance ( P<.001) and beta cell function ( P<.001) explained 31.9% of the variability in 2-hour glucose concentration in a multivariable model (total model P<.001). VAT was associated with glucose metabolism to a larger degree than BMI. In conclusion, VAT is associated with hyperglycemia one year after kidney transplantation, and insulin resistance and beta cell function estimates are the most robust markers of glucose metabolism. [ABSTRACT FROM AUTHOR]

Aim Optimal tacrolimus exposure in transplant recipients is not well established. The results from the Symphony study indicated that low-target tacrolimus (trough concentrations 3-7 µg/L) in de novo standard risk renal transplant recipients should be appropriate. The aim of this study was to evaluate real-life outcomes when applying a similar strategy in a clinical setting. Methods A single-centre analysis was conducted in standard risk renal transplant recipients receiving low-target tacrolimus, mycophenolate mofetil, glucocorticoids and basiliximab induction. One-year estimated glomerular filtration rate (eGFR, Cockcroft-Gault), one-year biopsy-proven acute rejection rate and graft- and patient survival up to 3 years post-transplant were compared with the outcomes in the Symphony study. Results From 1 January 2009 to 31 March 2013, we included 406 patients. One year after transplantation, the mean ± SD eGFR was 76.8 ± 28.3 mL/min (Symphony: 65.4 ± 27.0 mL/min, P < 0.001). Biopsy-proven acute rejections were seen in 14.5% of the patients (Symphony: 12.3%, P = 0.35). Kaplan-Meier estimates [95% confidence interval] of three-year death-censored graft- and patient survival were 96.6% [94.2-99.0%] (Symphony: 93%) and 95.0% [92.6-97.3%] (Symphony: 95%), respectively. Conclusion Low-target tacrolimus-based immunosuppression is safe and effective also in a standard clinical setting in de novo standard risk renal transplant recipients. [ABSTRACT FROM AUTHOR]

Uric acid is associated with increased mortality in kidney transplant recipients (KTRs), but it is uncertain if this involves endothelial dysfunction. We hypothesized, first, that there was an association between uric acid and endothelial function, and second, that there were associations between endothelial function and cardiac and mortality risk scores. Methods One hundred and fifty-two patients were examined 10 wk after kidney transplantation by two measures of endothelial function, the brachial artery flow-mediated dilatation ( FMD) expressed as percent dilatation ( FMD%), and fingertip peripheral arterial tone (PAT) expressed as log-reactive hyperemia index (Ln RHI). Risk scores were calculated from a recently validated formula. Other clinical correlates of endothelial function were described in stepwise linear regression models. Results Uric acid was associated negatively with FMD% in an age- and gender-adjusted model, while not in the multivariable model. No association was shown between uric acid and Ln RHI. FMD% was associated negatively with risk scores in both crude and age- and gender-adjusted models (p < 0.01). Ln RHI was associated negatively with risk scores in the latter model only (p < 0.05). Conclusions Uric acid was neither associated with FMD% nor Ln RHI in KTRs. There were significant associations between endothelial function indices and cardiac and mortality risk scores. [ABSTRACT FROM AUTHOR]

AIMS The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models METHODS Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting. RESULTS Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h-1 [95% CI 12.6, 18.0 l h-1]. Tacrolimus clearance was 30% higher (95% CI 13,46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of -1.2% (95% CI -3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range. CONCLUSION A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation. [ABSTRACT FROM AUTHOR]

Long-term triple immunosuppressive therapy with cyclosporine ( Cs A), mycophenolate mofetil ( MMF) and prednisolone may be excessively powerful for many transplant recipients. We compared withdrawal of either MMF or Cs A in stable kidney transplants on triple immunosuppression. The study was a prospective, randomized, controlled 12-months trial in stable kidney transplants. The patients who withdrew Cs A were given MMF 2 g/d, and Cs A troughs were between 75 and 125 ng/mL in MMF withdrawal. Planned inclusion was 298 patients. The study was prematurely aborted after inclusion of 39 patients. Acute rejection rates were 6/20 (30%) in the MMF group compared with 0/19 (0%) in the Cs A group (p = 0.02). Time to acute rejections was 4.0-28.7 months after withdrawal. Trough concentrations of mycophenolic acid ( MPA) and Cs A showed therapeutic levels. The subjects have been observed for eight yr, and of the 28 patients remaining on randomized therapy, the MMF patients preserved graft function better than Cs A patients. Death-censored graft survival was 75% and 95% (p = 0.18) and patient survival was 70% and 68% (p = 0.99) in the MMF and Cs A groups, respectively, at the end of long-term follow-up. Cs A withdrawal was associated with a high rate of acute rejections. Initially, the treatment of acute rejections was successful. However, five of six lost their grafts in the long term. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitors (CNI) are involved in the development of post-transplant diabetes mellitus (PTDM). Changes in insulin secretion and sensitivity contribute to the development of PTDM and are associated with endothelial function. Methods: In a pre-defined substudy of a previously published randomized trial in renal transplant recipients we compared the effect of CNI treatment (n = 23) with complete CNI-avoidance (n = 21) on insulin secretion and sensitivity (oral glucose tolerance test) as well as endothelial function (laser Doppler flowmetry), 10 wk and 12 months following transplantation. Results: Insulin sensitivity differed 10 wk post-transplant and was significantly better after 12 months in patients never treated with CNI drugs [0.091 (0.050) vs. 0.083 (0.036) μmol/kg/min/pmol/L, p = 0.043]. Insulin secretion tended to be higher in CNI treated patients at both time points (p = 0.068). Endothelial function was not significantly different at week 10 [540 (205) vs. 227 (565) arbitary units × minutes, p = 0.35] or month 12 [510 (620) vs. 243 (242), p = 0.33]. Conclusions: Findings in the present study indicate that long-term CNI treatment negatively affects glucose metabolism and this may contribute to the increased risk for premature cardiovascular disease in CNI treated renal transplant recipients. Further studies to elucidate this hypothesis are, however, needed. [ABSTRACT FROM AUTHOR]

Background: The most serious side effect from statin treatment is myopathy, which may proceed to rhabdomyolysis. This is the first study to investigate whether the pharmacokinetics of either atorvastatin or its metabolites, or both, is altered in patients with atorvastatin-related myopathy compared with healthy controls.Methods: A 24-hour pharmacokinetic investigation was performed in 14 patients with atorvastatin-related myopathy. Relevant polymorphisms in SLCO1B1 (encoding organic anion transporting polypeptide 1B1), MDR1/ABCB1 (encoding P-glycoprotein), and CYP3A5 (encoding cytochrome P450 3A5) were determined. Data from 15 healthy volunteers were used as controls.Results: No statistically significant difference in systemic exposure of atorvastatin was observed between the 2 groups. However, patients with atorvastatin-related myopathy had 2.4-fold and 3.1-fold higher systemic exposures of the metabolites atorvastatin lactone (P < .01) and p-hydroxyatorvastatin (P < .01), respectively, compared with controls. There were no differences in frequencies of SLCO1B1, MDR1, and CYP3A5 polymorphisms between the 2 groups.Conclusions: This study disclosed a distinct difference in the pharmacokinetics of atorvastatin metabolites between patients with atorvastatin-related myopathy and healthy control subjects. These results are of importance in the further search for the mechanism of statin-induced myopathy.Clinical Pharmacology & Therapeutics (2006) 79, 532–539; doi: 10.1016/j.clpt.2006.02.014 [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is a common finding in renal transplant recipients (RTR) and is related to impaired local regulation of vasodilative and vasoconstrictive substances, such as nitric monoxide (NO) and endothelin-1 (ET-1). In non-transplanted patients, an association between impaired endothelial function and insulin resistance has been shown. Whether such an association also exists in RTR is unknown. Objective: The aim of the present study was to examine whether insulin resistance is associated with endothelial dysfunction in RTR. Material and methods: A total of 47 RTR in a stable phase six yr post-transplant were included in the statistical analysis. The immunosuppressive therapy was based on cyclosporine and prednisolone. Non-invasive assessment of endothelial function was performed with laser Doppler flowmetry of the forearm skin vasculature after local acetylcholine stimulation. Oral glucose tolerance tests comprising both glucose and insulin measurements were used to calculate insulin sensitivity (IS) indices. NO, ET-1 and von Willebrand factor were measured in fasting plasma samples. Results: Normal glucose tolerance was found in 31 RTR. In these subjects, both IS (r2=0.164, p=0.044) and plasma NO (r2=0.326, p=0.002) were significantly correlated with endothelial function. Patients with glucose intolerance (n=16) had higher plasma ET-1 and lower NO levels, but the association between IS and endothelial function was not significant in these subjects. In the total patient cohort, IS and endothelial function tended to be correlated (p=0.127). Conclusions: Endothelial dysfunction is significantly associated with insulin resistance in normoglycemic RTR but explains a rather small part of the variation. In glucose-intolerant recipients, IS appears to be more critically dependent on other factors not revealed in the present study. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cardiovascular risk is greatly increased in renal transplant recipients. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy may reduce cardiovascular risk by improving both dyslipidemia and endothelial function. We therefore performed this study to assess the effect of fluvastatin on endothelial function in renal transplant recipients. Methods: This randomized, placebo-controlled, double-blind designed study investigated the effect of fluvastatin on endothelial function. Thirty-seven recipients received fluvastatin 40 mg/d and 35 received placebo during the first 12 wk following transplantation. All patients initially received cyclosporin A, prednisolone and azathioprine. At the end of treatment, endothelial function was assessed in the forearm skin microvasculature by laser Doppler flowmetry following acetylcholine stimulation. Samples were taken for measurements of serum lipids and vasoactive markers. Results: There were no differences in endothelial function between fluvastatin recipients and controls, AUCACh was 656 ± 479 and 627 ± 518 AU min, respectively (fluv vs. control, p > 0.65). In the placebo limb, total cholesterol and LDL cholesterol increased 22 ± 12% and 22 ± 18%, respectively in the first 12 wk following transplantation. The respective values were 18 ± 13% (p = 0.010) and 34 ± 19% (p = 0.0013) lower at 12 wk in the fluvastatin treated patients. Plasma ET-1, BigET-1 and urinary excretion of cGMP were not significantly different between treatment groups (p > 0.55). Conclusion: Although fluvastatin 40 mg/d significantly lowers cholesterol it does not affect endothelial function the first 3 months after renal transplantation. The lack of effect on endothelial function is consistent with a lack of effect on vasoactive substances. [ABSTRACT FROM AUTHOR]

Why dose adjust systemic exposure when looking for associations with adverse events in tacrolimus-treated transplant recipients? Keywords: adverse drug reactions; drug metabolism; other; pharmacokinetics; transplantation EN adverse drug reactions drug metabolism other pharmacokinetics transplantation 2535 2535 1 11/28/20 20201201 NES 201201 The article by Campagne et al1 highlights a timely issue in modern immunosuppressive therapy of transplanted patients; what is the impact of tacrolimus (Tac) exposure on extrarenal adverse effects? Adverse drug reactions, drug metabolism, other, pharmacokinetics, transplantation. [Extracted from the article]

We appreciate the input of Drs Yildiz and Yildiz.[1] They suggest an addition to our review on the bioavailability of immunosuppressive drugs after bariatric surgery,[2] specifically in relation to transplantation surgery. Our general recommendation would therefore be to use standard TDM procedure in patients transplanted after bariatric surgery and to intensify TDM in case of bariatric surgery in transplanted patients. [Extracted from the article]

Background: Short‐term survival after kidney transplantation is excellent, but long‐term survival remains low and is equivalent to non‐end‐stage renal disease patients with many invasive malignancies. The aim of the study was to explore vitamin D status in the early phase after transplantation as a prognostic marker for long‐term graft and patient survival. Methods: All first‐time kidney transplant recipients between October 2007 and October 2012 in Norway were included. Vitamin D was measured 10 weeks post‐transplant. Information on graft failure and death was obtained from the Norwegian Renal Registry. Results: Seven hundred and sixty‐two first‐time kidney transplant recipients were included, with a median age of 57 years and a median follow‐up of 82 months. In the follow‐up period, there were 172 graft failures (23%) and 118 deaths (15%). Eighty‐six percent of the transplant recipients with sufficient vitamin D levels were alive with a well‐functioning graft after 5 years using Kaplan‐Meier survival estimates, compared with 79% and 76% of the patients with vitamin D deficiency and insufficiency, respectively (P = 0.006). Conclusion: In a nation‐wide cohort of 762 first‐time kidney transplant recipients, long‐term graft and patient survival were better in recipients with vitamin D sufficiency 10 weeks post‐transplant compared with those with vitamin D deficiency and insufficiency. [ABSTRACT FROM AUTHOR]