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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]

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]

In some parts of the world, high intake of marine omega-3 FAs is recommended for the general population and it is likely that RTRs use omega-3 FA supplements without consulting a transplant physician [2]. Doses were kept unchanged between the two sub-study pharmacokinetic investigations. gl The main finding in the present study was that the systemic exposure of once-daily tacrolimus was increased on average by 25% after daily high-dose marine omega-3 FA supplementation. Physicians should be aware that this clinically relevant increase in the systemic exposure of tacrolimus may not necessarily induce a similar increase in trough concentrations [10], which make it difficult to monitor tacrolimus levels following the initiation and discontinuation of marine omega-3 FA supplementation. [Extracted from the article]

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]

Aims: The aim of this population-based historical cohort study was to investigate the influence of lifestyle factors on the risk of developing migraine or tension-type headache (TTH).Methods: Data from the Nord-Trøndelag Health Study performed in 1995-1997 and 2006-2008 was used. A total of 15,276 participants without headache at baseline were included. A Poisson regression was used to evaluate the associations between lifestyle factors and risk ratios (RRs) of migraine and TTH 11 years later. Precision of the estimates was assessed by 95% confidence interval (CIs).Results: Increased risk of migraine (RR 1.30, 95% CI 1.11-1.52) was found in smokers (past or current) compared to those who had never smoked. Hard physical exercise 1-2 hours per week reduced the risk of migraine (OR 0.71, 95% CI 0.54-0.94) compared to inactivity, and the risk of migraine was also lower among those who consumed alcohol (RR 0.73, 95% CI 0.57-0.94) compared to abstainers. No association was found between smoking, physical activity, alcohol use and risk of TTH.Conclusions: The main finding was that current and previous smoking was associated with increased risk of migraine, but not of TTH. [ABSTRACT FROM AUTHOR]

Background: Musculoskeletal complaints (MSC) are common in the general population, causing a major disease burden to the individual and society. The association between MSC and mortality is still unclear. To our knowledge, no study has hitherto evaluated the association between MSC onset within the last month (incident MSC) on the one hand, and all-cause and cause-specific mortality on the other. Methods: This prospective population-based cohort study was done using data from the second Nord-Trøndelag Health Study (HUNT2) linked with data from a comprehensive national registry of cause of death. A total of 25,931 participants at risk for incident MSC were included. Hazard ratios (HR) of mortality were estimated for participants with incident MSC using Cox regression based on a mean of 14.1 years of follow-up. Results: Participants who reported incident MSC did not have an excess mortality compared to those with no MSC in the analyses of all-cause mortality (HR 0.99, 95% CI 0.89–1.10) and cause specific mortality. This was true also after adjustment for several potential confounding factors. No clear association between the number of MSC body sites and mortality was found. Conclusion: Incident MSC were not associated with an increased mortality, neither for all-cause mortality, nor cause-specific mortality. [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]

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]

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]

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]

The impact of chronic musculoskeletal complaints (CMSC) and chronic widespread chronic musculoskeletal complaints (CWMSC) on mortality is controversial. The aim of this study was to investigate the relationship between these conditions and mortality. In this prospective population-based cohort study from Norway, baseline data from the second Nord-Trøndelag Health Survey (HUNT2, performed 1995-1997) were linked to the comprehensive National Cause of Death Registry in Norway with follow-up through the year 2011. A total of 65,026 individuals (70%) participated and were categorized based on their response to CMSC questions in HUNT2 (no CMSC, CMSC, or CWMSC). Hazard ratios (HRs) of mortality during a mean of 14.1 years of follow-up were estimated using Cox regression. During the follow-up period, 12,521 subjects died, 5162 from cardiovascular diseases, 3478 from cancer, and 3881 from all other causes. In the multivariate-adjusted analyses, there was no difference in all-cause mortality between individuals with or without CMSC (HR 1.01, confidence interval, 0.97-1.05) and CWMSC (HR 1.01, confidence interval, 0.96-1.05). Similarly, there was no association between CMSC or CWMSC and cardiovascular mortality, mortality from cancer, or mortality from all other causes. Therefore, from this study, we conclude that there is no evidence for a higher mortality rate among individuals with CMSC or CWMSC. [ABSTRACT FROM AUTHOR]

The VICTOR study showed comparable efficacy of treatment with intravenous ganciclovir and oral valganciclovir for cytomegalovirus (CMV) disease in solid organ transplant recipients. Oral therapy is now recommended treatment in clinical practice and guidelines. The VICTOR biobank was used in a series of post hoc analyses that yielded unique and clinically valuable insights into CMV treatment and pathogenesis. For example, the importance of tailoring therapy to initial viral load, the effect of immunosuppression on outcomes, and the need to continue therapy until undetectable viral load to prevent recurrence and emergence of resistant strains. Data were also used to validate the use of international units (IU) in quantitative measurements of CMV DNAemia, which may help future studies to define relevant cutoffs for treatment guidance. The analyses also showed the importance of inflammation on viral outcomes and identified potential targets for future studies. Here we summarize the valuable lessons learned from analysis of the VICTOR data set and sample repository. [ABSTRACT FROM AUTHOR]

Background: There is conflicting evidence for the association between migraine and increased mortality risk. The aim of this study was to investigate the relationship between migraine and non-migrainous headache, and all-cause mortality and cardiovascular mortality.Methods: In this prospective population-based cohort study from Norway, we used baseline data from the second Nord-Trøndelag Health Survey (HUNT2), performed between 1995 and 1997 in the County of Nord-Trøndelag. These data were linked with a comprehensive mortality database with follow-up through the year 2011. A total of 51,853 (56% of invited) people were categorized based on their answers to the headache questions in HUNT2 (headache free, migraine or non-migrainous headache). Hazard ratios (HRs) of mortality during a mean of 14.1 years of follow-up were estimated using Cox regression.Results: During the follow-up period 9408 died, 4321 of these from cardiovascular causes. There was no difference in all-cause mortality between individuals with migraine and non-migrainous headache compared to those without headache or between headache status and mortality by cardiovascular disease. There was, however, among men with migraine without aura a reduced risk of death by cardiovascular diseases (HR 0.72, 95% confidence interval 0.56-0.93). This relationship was not evident in women.Conclusion: In this large, prospective cohort study there was no evidence for a higher all-cause mortality or cardiovascular mortality among individuals with migraine. [ABSTRACT FROM AUTHOR]

Background: Post-transplant diabetes mellitus is one of the most important cardiovascular risk factors after solid organ transplantation. Factors other than hyperglycaemia found in patients post-transplant, affect the level of haemoglobin A1c (HbA1c), and new markers of hyperglycaemia are needed. Our aim was to establish a 95% reference interval for glycated albumin in kidney transplant recipients, and to compare glycated albumin concentrations to the diagnostic criteria for diabetes mellitus post-transplant using oral glucose tolerance test and HbA1c. Methods: A total of 341 non-diabetic kidney transplant recipients aged ≥18 years who underwent an oral glucose tolerance test at 8 weeks and 1 year after transplantation were included. Glycated albumin was determined by liquid chromatography coupled with tandem mass spectrometry. Results: The 95% reference interval for glycated albumin was 8.2 (90% CI: 7.2–8.5) to 12.8% (90% CI: 12.2–13.5) which is not significantly different from our laboratory's 95% reference interval for persons without diabetes. At both 8 weeks and 1 year after transplantation, 35 patients (10.3%) fulfilled one, two or all three diagnostic criteria for diabetes mellitus. One year after transplantation, eight additional patients had glycated albumin concentration >12.8%. Conclusion: Our findings are in accordance with the notion that kidney transplant recipients form glycation end products like normal controls as estimated by glycated albumin and HbA1c. Further studies should address glycated albumin as a supplemental tool for the diagnosis of post-transplant diabetes mellitus in kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Background New-onset diabetes after transplantation (NODAT) is a common complication after renal transplantation. There are limited available oral drugs to treat hyperglycaemia in this population owing to reduced renal function, potential interactions with immunosuppressive drugs and adverse effects such as hypoglycaemic events that may increase the cardiovascular risk. This study was initiated to investigate efficacy and safety of sitagliptin treatment that may represent a novel alternative in renal transplant recipients. Methods Nineteen long-term stable renal transplant recipients with NODAT were included in a controlled, cross-over study and randomized to first receive either sitagliptin 50–100 mg/day or a sitagliptin-free period of 4 weeks. Median age (interquartile range, IQR) was 67 (62–72) years (12 males/7 females), all studied 1 (1–3) year after transplantation. The immunosuppressive regimen was a triple calcineurin inhibitor-based therapy. Oral glucose tolerance test (OGTT) with insulin and C-peptide responses and laser Doppler (LD) flowmetry assessment of endothelial function were performed at baseline and after each treatment period. Home measurements of plasma glucose were performed daily during the study. Results The median (IQR) first- and second-phase insulin secretion responses increased significantly by 56.3% (45.2–112.6%, P = 0.005) and 39.3% (26.5–81.0%, P = 0.006), respectively, following sitagliptin treatment as compared with no sitagliptin treatment. Fasting and 2-h plasma glucose concentrations fell significantly {0.9 mmol/L [0.5–1.7 mmol/L (16.2 mg/dL), P = 0.003] and 2.9 mmol/L [0.5–6.4 mmol/L (52.3 mg/dL), P = 0.004], respectively}, as did also home measurements of plasma glucose. Endothelial function and plasma markers of cardiovascular risk were unaffected. No serious adverse events were observed. Two mild and asymptomatic hypoglycaemic episodes were observed in combination with glipizide. Conclusions Sitagliptin increases insulin secretion and reduces fasting and postprandial plasma glucose in renal transplant recipients with NODAT. The short-term treatment was well tolerated, and sitagliptin seems safe in this population. [ABSTRACT FROM AUTHOR]

Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C0 concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three-compartment model with first-order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat-free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3-4 tacrolimus concentrations were known. After this, a model without CYP3 A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation. [ABSTRACT FROM AUTHOR]

This clinical trial of a cytomegalovirus (CMV) DNA test standardized to the First World Health Organization International Standard for CMV in solid organ transplant patients undergoing treatment for CMV disease found that viral suppression is predictive of shorter time to CMV disease resolution.Background. Cytomegalovirus (CMV) load measurement is used to assess the efficacy of treatment of CMV disease, but lacks standardization. Using the World Health Organization (WHO) international standard for reporting, we correlated viral load with CMV disease resolution.Methods. CMV load was quantified in plasma using a test calibrated to the WHO standard. Three predictive rules were predefined to determine association between CMV DNAemia and outcome: (1) pretreatment CMV DNA of <18 200 (4.3 log10) IU/mL; (2) viral load declines of 1.0, 1.5, 2.0, and 2.5 log10 IU/mL from baseline to days 7, 14, and 21 of treatment, respectively; and (3) viral suppression <137 (2.1 log10) IU/mL at days 7, 14, and 21. Analysis was performed using Cox proportional hazard models.Results. Of 267 patients, 251 had CMV disease resolution by day 49 of treatment. Patients with pretreatment CMV DNA of <18 200 (4.3 log10) IU/mL had faster time to disease resolution (adjusted hazard ratio [AHR], 1.56; P = .001). Patients with CMV load suppression (<137 IU/mL [<2.1 log10]) at days 7, 14, and 21 had faster times to clinical disease resolution (AHRs, 1.61, 1.73, and 1.64, and P = .005, <.001, and <.001, respectively). Relative CMV load reductions from baseline were not significantly associated with faster resolution of CMV disease.Conclusions. Patients with pretreatment CMV DNA of <18 200 (4.3 log10) IU/mL are 1.5 times more likely to have CMV disease resolution. CMV suppression (<137 [2.1 log10] IU/mL), as measured by a test calibrated to the WHO Standard, is predictive of clinical response to antiviral treatment.Clinical Trials Registration. NCT00431353. [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]

Abstract: Proteolytic 18O-labeling of peptides has been studied and optimized in order to improve the labeling efficiency and to accelerate the process without increasing the degree of incomplete labeling. Using peptides generated from tryptic digested bovine serum albumin (BSA) and cytochrome c as model proteins, it was shown that complete labeling was achieved after 2h at pH 6. To increase the sample throughput in a bottom-up proteomic setup, tryptic digestion of proteins in-solution was replaced with tryptic digestion using immobilized trypsin. As a result, an integrated approach was made possible, where both digestion (pH 8) and 18O/16O-labeling of the resulting peptides (pH 6) were done using immobilized trypsin beads. This simplified the sample handling and reduced the overall reaction time significantly: the setup enabled tryptic digestion and 18O/16O-labeling without sample transfer steps within 3.5h with average 18O/16O-ratios of 0.96±0.13 in aqueous buffer. The initial results were confirmed with a more complex matrix, by spiking urine with the model proteins, yielding results comparable with the ratios obtained in buffer. Satisfying ratios were also achieved regarding urinary proteins identified in a full scale bottom-up experiment. Average 18O/16O-peptide ratios of 0.83±0.13 and 0.91±0.27 indicated good performance in a highly relevant matrix for biomarker discovery. [ABSTRACT FROM AUTHOR]

Background. It is unknown whether specific viral polymorphisms affect in vivo therapeutic response in patients with cytomegalovirus (CMV) disease. Polymorphisms in the CMV glycoprotein B (gB) gene allow discrimination of 4 distinct genotypes (gB1-gB4). We assessed the influence of gB genotypes on the clinical and virologic outcome of CMV disease. Methods. Solid-organ transplant recipients enrolled in a multicenter trial of CMV disease treatment (VICTOR study) were included in this study. CMV gB genotyping was performed using quantitative real-time polymerase chain reaction at day 0 (start of antiviral therapy). Results. Among 239 patients with CMV disease, the prevalence of gB strain types was 26% for gB1, 10% for gB2, 10% for gB3, and 5% for gB4, whereas mixed infections were present in 49%. Donor-seropositive/recipientseropositive patients were more likely to have mixed gB infection than donor-seropositive/recipient-seronegative patients (40% vs. 12%; ). Median baseline viral P < .001 loads were higher and time to viral eradication was longer (P = .005 and Pp.026, respectively) for mixed infection versus infection with a single genotype. In a multivariate model, mixed gB infection was a significant predictor of failure to eradicate virus by day 21 (mixed vs single genotype; odds ratio, 2.66; 95% confidence interval, 1.31-5.38; P = .007) after controlling for baseline viral load, CMV serostatus at baseline, ganciclovir resistance, and antiviral treatment. No effect of gB genotype was seen on virologic or clinical CMV recurrence. Conclusions. No specific gB genotype appears to confer a specific CMV virulence advantage. However, mixed gB genotype infections are associated with higher viral loads and delayed viral clearance. [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]

Abstract: The aim of the present study was to develop a time-efficient chromatographic method for the analysis of therapeutic concentrations of ganciclovir (GCV) in plasma, urine as well as dialysate (from continuous renal replacement therapy) from solid organ transplant recipient treated with either GCV or its prodrug valganciclovir (VGCV) in combination with a wide variety of other concomitant drugs. Sample preparation was performed by reversed phase solid phase extraction and was followed by separation of the analytes on a reversed phase column using isocratic elution with a mobile phase consisting of acetonitrile—a counter ion (50mM 1-heptanesulfonic acid) in an aqueous sodium dihydrogen phosphate buffer (pH 2.1; 10mM) (10:90 v/v) and a fluorescence detector. Validation of the method showed linearity within the concentration range of 0.1–40μg/mL for plasma and 0.1–120μg/mL for urine and dialysate (R 2 >0.99, n ≥5). Accuracy and precision (evaluated at 0.1, 5 and 40μg/mL) were both satisfactory. The LLOQ was determined to be 0.1μg/mL. The method was successfully applied on clinical samples from renal transplant recipients treated with VGCV in combination with a variety of usually used concomitant drugs for solid organ transplant recipients. [Copyright &y& Elsevier]

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]

The aim of the present study was to evaluate the possible influence of atorvastatin on the pharmacokinetics of cyclosporine (INN ciclosporin) and its main metabolites, AM1 and AM9, in renal transplant recipients. Whole blood samples from 18 renal transplanted patients on cyclosporine-based immunosuppressive therapy were collected prior to and after 4 weeks of treatment with atorvastatin (10 mg/day) and analysed with regard to both cyclosporine and its main metabolites, AM1 and AM9, using a specific chromatographic method with ultraviolet detection. On average, AUC0-12 [area under the whole blood concentration versus time curve in the dosing interval (0-12 h)] of cyclosporine was 5% (16, 5) (90% confidence interval) lower upon co-administration with atorvastatin. No statistically significant changes in any of the calculated pharmacokinetic variables [AUC0-12, maximum whole blood concentration (Cmax), whole blood concentration 12 h post dose (C12), time to Cmax (tmax), terminal half-life (t1/2)] for cyclosporine or the two metabolites, AM1 and AM9, upon atorvastatin treatment were observed. On average, atorvastatin did not affect the ratio between the CYP3A4-mediated metabolite AM9 and cyclosporine, suggesting that atorvastatin does not affect the CYP3A4 metabolism of cyclosporine to any significant extent. However, the influence of atorvastatin on the ratio between AM9 and cyclosporine showed large interindividual variability. The results of this study indicate that atorvastatin does not, on average, affect cyclosporine pharmacokinetics in renal transplant recipients. [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]

Plasma total cysteine (tCys) is strongly associated with fat mass in humans. Mesna lowers plasma tCys in a dose-dependent manner, but it is not known whether it interferes with metabolism of other amino acids or protein. In this Phase-1 study, we show that a single dose of mesna administered at 400, 800, 1200 or 1600 mg to 6–7 individuals per dose only slightly affects amino acid profiles, with increases in plasma valine across dose levels. There were no effects of mesna on 3-methylhistidine, a marker of protein breakdown. [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]

Background and Objective: Given a high pharmacokinetic inter-individual variability and a low exposure target achievement, ganciclovir (GCV) therapeutic drug monitoring is sometimes used in children. We aimed to develop and validate Bayesian estimators based on limited sampling strategies for the estimation of GCV area under the concentration–time curve from 0 to 24 h in pediatric transplant recipients treated with valganciclovir (VGCV) or GCV. Methods: Solid organ transplant or stem-cell transplant recipients who received GCV or VGCV and had available GCV concentrations per standard of care were retrospectively included in this study for pharmacokinetic modeling and development of Bayesian estimators using the iterative two-stage Bayesian method. Validation datasets included additional child recipients of a solid organ transplant or stem-cell transplant, and child recipients of a kidney or liver transplant enrolled in a previous study. Various combinations of three or two sampling times, applicable in clinical practice, were assessed based on the relative mean bias, standard deviation, and the root mean square error in a development dataset and three independent validation datasets. Results: In the development dataset, the mean bias/standard deviation/root mean square error for the 1 h/2 h/3 h and 1 h/3 h limited sampling strategies were − 1.4%/9.3%/9.1% and − 3.5%/12.2%/12.3%, respectively for GCV, while for VGCV, the mean bias/standard deviation/root mean square error for the 1 h/2 h/6 h and 1 h/6 h limited sampling strategies were 0.7%/13.5%/13.3% and − 0.1%/12.1%/11.8%, respectively. In the independent validation datasets, seven (13%) and five (14%) children would have had misclassifications of their exposure using these Bayesian estimators and limited sampling strategies for VGCV and GCV, respectively. Conclusions: Three plasma samples collected at 1 h/2 h/3 h and 1 h/2 h/6 h post-dose for GCV and VGCV respectively, are sufficient to accurately determine GCV area under the concentration–time curve from 0 to 24 h for pharmacokinetic-enhanced therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Background and Objectives: Ganciclovir (GCV) and valganciclovir (VGCV) show large interindividual pharmacokinetic variability, particularly in children. The objectives of this study were (1) to develop machine learning (ML) algorithms trained on simulated pharmacokinetics profiles obtained by Monte Carlo simulations to estimate the best ganciclovir or valganciclovir starting dose in children and (2) to compare its performances on real-world profiles to previously published equation derived from literature population pharmacokinetic (POPPK) models achieving about 20% of profiles within the target. Materials and Methods: The pharmacokinetic parameters of four literature POPPK models in addition to the World Health Organization (WHO) growth curve for children were used in the mrgsolve R package to simulate 10,800 pharmacokinetic profiles. ML algorithms were developed and benchmarked to predict the probability to reach the steady-state, area-under-the-curve target (AUC0–24 within 40–60 mg × h/L) based on demographic characteristics only. The best ML algorithm was then used to calculate the starting dose maximizing the target attainment. Performances were evaluated for ML and literature formula in a test set and in an external set of 32 and 31 actual patients (GCV and VGCV, respectively). Results: A combination of Xgboost, neural network, and random forest algorithms yielded the best performances and highest target attainment in the test set (36.8% for GCV and 35.3% for the VGCV). In actual patients, the best GCV ML starting dose yielded the highest target attainment rate (25.8%) and performed equally for VGCV with the Franck model formula (35.3% for both). Conclusion: The ML algorithms exhibit good performances in comparison with previously validated models and should be evaluated prospectively. [ABSTRACT FROM AUTHOR]

Background The European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with end-stage kidney disease (ESKD). This paper is a summary of the ERA Registry Annual Report 2021, including a comparison across treatment modalities. Methods Data was collected from 54 national and regional registries from 36 countries, of which 35 registries from 18 countries contributed individual patient data and 19 registries from 19 countries contributed aggregated data. Using this data, incidence and prevalence of KRT, kidney transplantation rates, survival probabilities and expected remaining lifetimes were calculated. Result In 2021, 533.2 million people in the general population were covered by the ERA Registry. The incidence of KRT was 145 per million population (pmp). In incident patients, 55% were 65 years or older, 64% were male, and the most common primary renal disease (PRD) was diabetes (22%). The prevalence of KRT was 1040 pmp. In prevalent patients, 47% were 65 years or older, 62% were male, and the most common PRDs were diabetes and glomerulonephritis/sclerosis (both 16%). On 31 December 2021, 56% of patients received haemodialysis, 5% received peritoneal dialysis, and 39% were living with a functioning graft. The kidney transplantation rate in 2021 was 37 pmp, a majority coming from deceased donors (66%). For patients initiating KRT between 2012–2016, 5-year survival probability was 52%. Compared to the general population, life expectancy was 65% and 68% shorter for males and females receiving dialysis, and 40% and 43% shorter for males and females living with a functioning graft. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide Background Literature on recovery of kidney function (RKF) in patients with end-stage kidney disease treated with maintenance dialysis (i.e. >90 days) is limited. We assessed the incidence of RKF and its associated characteristics in a European cohort of dialysis patients. Methods We included adult patients from the European Renal Association–European Dialysis and Transplant Association Registry who started maintenance dialysis in 1997–2016. Sustained RKF was defined as permanent discontinuation of dialysis. Temporary discontinuation of ≥30 days (non-sustained RKF) was also evaluated. Factors associated with RKF adjusted for potential confounders were studied using Cox regression analyses. Results RKF occurred in 7657 (1.8%) of 440 996 patients, of whom 71% experienced sustained RKF. Approximately 90% of all recoveries occurred within the first 2 years after Day 91 of dialysis. Of patients with non-sustained RKF, 39% restarted kidney replacement therapy within 1 year. Sustained RKF was strongly associated with the following underlying kidney diseases (as registered by the treating physician): tubular necrosis (irreversible) or cortical necrosis {adjusted hazard ratio [aHR] 20.4 [95% confidence interval (CI) 17.9–23.1]}, systemic sclerosis [aHR 18.5 (95% CI 13.8–24.7)] and haemolytic uremic syndrome [aHR 17.3 (95% CI 13.9–21.6)]. Weaker associations were found for haemodialysis as a first dialysis modality [aHR 1.5 (95% CI 1.4–1.6)] and dialysis initiation at an older age [aHR 1.8 (95% CI 1.6–2.0)] or in a more recent time period [aHR 2.4 (95% CI 2.1–2.7)]. Conclusions Definitive discontinuation of maintenance dialysis is a rare and not necessarily an early event. Certain clinical characteristics, but mostly the type of underlying kidney disease, are associated with a higher likelihood of RKF. [ABSTRACT FROM AUTHOR]

Background: Questionnaire-based headache diagnoses should be validated against diagnoses made by the gold standard, which is personal interview by a headache expert. The diagnostic algorithm with the best diagnostic accuracy should be used when later analysing the data. Methods: The Nord-Trøndelag Health Study (HUNT4) was performed between 2017 and 2019. Among HUNT4 participants, a total of 232 (19.3%) out of 1201 randomly invited were interviewed by a headache expert to assess the sensitivity, specificity and kappa value of the questionnaire-based headache diagnoses. Results: The median interval between answering the headache questions and the validation interview was 60 days (95% CI 56–62 days). The best agreements were found for self-reported lifetime migraine (sensitivity of 59%, specificity of 99%, and a kappa statistic of 0.65, 95% CI 0.55–0.75), self-reported active migraine (sensitivity of 50%, specificity of 97%, and a kappa statistic of 0.55, 95% 0.39–0.71), liberal criteria of migraine (sensitivity of 64%, specificity of 93%, and a kappa statistic of 0.58, 95% CI 0.43–0.73) and ICDH3-based migraine ≥1 days/month (sensitivity of 50%, specificity of 94%, and a kappa statistic of 0.49, 95% CI 0.30–0.68). For headache suffering ≥1 days/month a sensitivity of 90%, specificity 80%, and a kappa statistic of 0.55, 95% CI 0.41–0-69 were found. For tension-type headache (TTH) ≥ 1 days/month the agreement was 0.33 (95% CI 0.17–0.49). Conclusion: The HUNT4 questionnaire is a valid tool for identifying persons with lifetime migraine, self-reported active migraine and active migraine applying liberal modified criteria. The agreement for TTH was fair. [ABSTRACT FROM AUTHOR]

Background and Objective: Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals. Methods: This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery. Results: The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 ± 2.3% and 11 ± 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration–time curve from zero to infinity in both groups: RYGB: 2.7 µg h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 µg h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 ± 0.33 hours at week 3 to 0.77 ± 0.08 hours at week 9 (−0.26 hours [95% CI −0.47, −0.05]), corresponding to a 25% reduction. Area under the concentration–time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 µg h/L [−0.94, 3.2]) or the diet group (0.94 µg h/L [−1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 ± 7%, diet: 3 ± 6%). At baseline, the area under the concentration–time curve from zero to infinity was −5.5 µg h/L [95% CI −8.5, −2.5] (−26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/µg [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals. Conclusions: Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) in children, from birth to late adolescence, is a unique and highly challenging condition that requires epidemiological research and large-scale, prospective cohort studies. Since its first launch in 2007, the European Society for Paediatric Nephrology/European Renal Association (ESPN/ERA) Registry has collected data on patients on kidney replacement therapy (KRT). However, slowing the progression of CKD is of particular importance and thus the possibility to extend the current registry dataset to include patients in CKD stages 4–5 should be a priority. A survey was sent to the national representatives within the ESPN/ERA Registry to collect information on whether they are running CKD registries. All the representatives from the 38 European countries involved in the ESPN/ERA Registry participated in the survey. Eight existing CKD registries have been identified. General characteristics of the national registry and detailed data on anthropometry, laboratory tests and medications at baseline and at follow-up were collected. Results provided by this survey are highly promising regarding the establishment of an ESPN CKD registry linked to the ESPN/ERA KRT registry and subsequently linking it to the ERA Registry with the same patient identifier, which would allow us to monitor disease progression in childhood and beyond. It is our belief that through such linkages, gaps in patient follow-up will be eliminated and patient-centred outcomes may be improved. [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]

Background: The primary aim of this cross-sectional population-based study was to evaluate the 1-year prevalence of common headache disorders by a face-to-face interview.Methods: The fourth wave of Nord-Trøndelag Health Survey (HUNT4) started in September 2017. The study was undertaken as part of a project mainly focusing on sleep disorders, where a total of 232 (19.3%) out of 1200 invited HUNT4 participants underwent a face-to-face headache interview.Results: The mean age of the 232 participants was 58.4 years (range 22-89). There were 71.6% (95% CI 65.7-77.4) who reported headache during the last year, and 18.5% (95% CI 13.5-23.6) had suffered from headache in the same period. The 1-year prevalence of tension-type headache (TTH) was 43.1% (95% CI 36.7-49.5), of idiopathic stabbing headache 34.1% (27.9-40.2), and of definite migraine 18.1% (95% CI 13.1-23.1). A total of 7.6% (95% CI 4.0-10.7%) had migraine with coexisting TTH. Lifetime prevalence of migraine was 32.8% (95% CI 26.7-38.8). Headache yesterday was reported by 12.1% (95% CI 7.9-16.3), and 5.6% (95% CI 2.6-8.6) had headache during the interview.Conclusion: In this population-based cross-sectional headache study performed by a face-to-face interview, the 1-year prevalence of TTH was 43.1% and of idiopathic stabbing headache 34.1%. A total of 18.1% had active migraine (18.1%), whereas the lifetime prevalence of migraine was 32.8%. [ABSTRACT FROM AUTHOR]

Background: A scoping review from 2021 identified a lack of studies on the incidence, prevention and management of hypoglycaemia in home-dwelling older people with diabetes. The aim of this study was to investigate the frequency and duration of hypoglycaemic episodes measured by continuous glucose monitoring (CGM) in older people with diabetes who received home care and who were treated with glucose-lowering medications, and to compare the frequency and duration of hypoglycaemic episodes between subgroups of the study population according to demographic and clinical variables. Methods: This was an observational study investigating the occurrence of hypoglycaemia in people with diabetes aged ≥ 65 years. Data were collected using blinded continuous glucose monitoring (CGM, iPro2) for 5 consecutive days. Frequency and duration of hypoglycaemic episodes were assessed using a sensor glucose cut-off value of 3.9 mmol/L. A blood sample for measurement of HbA1c and creatinine-based eGFR (CKD-EPI) was obtained during the monitoring period. Demographic and clinical data were collected from electronic patient records. Results: Fifty-six individuals were enrolled (median age 82 years and 52% were men). Of the 36 participants who were treated with insulin, 33% had at least one hypoglycaemic episode during the five-day period. Among 18 participants who neither used insulin nor sulfonylurea, but other glucose-lowering medications, 44% had at least one hypoglycaemicepisode. Of those with hypoglycaemic episodes, 86% lived alone. The median duration of the hypoglycaemia was 1 h and 25 min, ranging from 15 min to 8 h and 50 min. Conclusion: This study identified an unacceptably high number of unknown hypoglycaemic episodes among older home-dwelling people with diabetes receiving home care, even among those not using insulin or sulfonylurea. The study provides essential knowledge that can serve as a foundation to improve the treatment and care for this vulnerable patient group. The routines for glucose monitoring and other prevention tasks need to be considered more comprehensively, also, among those treated with glucose-lowering medications other than insulin. [ABSTRACT FROM AUTHOR]

Background The European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with ESKD. This paper is a summary of the ERA Registry Annual Report 2020, also including comparisons among primary renal disease (PRD) groups. Methods Data were collected from 52 national and regional registries from 34 European countries and countries bordering the Mediterranean Sea: 35 registries from 18 countries providing individual level data and 17 registries from 17 countries providing aggregated data. Using this data, KRT incidence and prevalence, kidney transplantation rates, expected remaining lifetimes and survival probabilities were calculated. Results A general population of 654.9 million people was covered by the ERA Registry in 2020. The overall incidence of KRT was 128 per million population (p.m.p.). In incident KRT patients, 54% were older than 65 years, 63% were men and the most common PRD was diabetes mellitus (21%). Regarding initial treatment modality in incident patients, 85% received haemodialysis (HD), 11% received peritoneal dialysis (PD) and 4% received a pre-emptive kidney transplant. On 31 December 2020, the prevalence of KRT was 931 p.m.p. In prevalent patients, 45% were older than 65 years, 60% were men and glomerulonephritis was the most common PRD (18%). Of these patients, 58% were on HD, 5% on PD and 37% were living with a kidney transplant. The overall kidney transplantation rate in 2020 was 28 p.m.p. with a majority of kidney grafts from deceased donors (71%). The unadjusted 5-year survival, based on incident dialysis patient from 2011–15, was 41.8%. For patients having received a deceased donor transplant, the unadjusted 5-year survival probability was 86.2% and for patients having received a living donor transplant it was 94.4%. When comparing data by PRD group, differences were found regarding the distribution of age groups, sex and treatment modality received. [ABSTRACT FROM AUTHOR]

Background and Objective: Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral blood mononuclear cells (PBMCs) in renal transplant recipients.Methods: Full whole blood and PBMC concentration-time profiles of everolimus were obtained from 12 stable renal transplant recipients on two different occasions, 4 weeks apart. The dataset was treated as 24 individual profiles and split into a development dataset (n = 20) and a validation dataset (n = 4). The pharmacokinetic model was developed using non-parametric modeling and its performances and those of the derived Bayesian estimator were evaluated in the validation set.Results: A structural two-compartment model with first-order elimination and two absorption phases described by a sum of two gamma distributions were developed. None of the tested covariates (age, sex, albumin, hematocrit, fat-free mass and genetic variants such as CYP3A5*1, ABCB1 haplotype, PPARA*42, PPARA*48, and POR*28) were retained in the final model. A limited sampling schedule of two whole blood samples at 0 and 1.5 h and one PBMC sample at 1.5 h post dose provided accurate estimates of the area under the plasma concentration-time curve (AUC) in comparison with the trapezoidal reference AUC (relative bias ± standard deviation = - 3.9 ± 10.6 and 4.1 ± 12.3% for whole blood and PBMC concentrations, respectively).Conclusion: The developed model allows simultaneous and accurate prediction of everolimus exposure in whole blood and PBMCs, and supplies a base for a feasible exploration of the relationships between intracellular exposure and therapeutic effects in prospective trials. [ABSTRACT FROM AUTHOR]

Objective: Successful simultaneous pancreas and kidney transplantation (SPK) or pancreas transplantation alone (PTA) restores glycemic control. Diabetes and impaired kidney function are common side effects of immunosuppressive therapy. This study addresses glucometabolic parameters and kidney function during the first year. Methods: We examined 67 patients with functioning grafts (SPK n = 30, PTA n = 37) transplanted between September 2011 and November 2016 who underwent repeated oral glucose tolerance tests (OGTTs) 8 and 52 weeks after transplantation. Another 19 patients lost their graft the first year post-transplant and 28 patients did not undergo repeated OGTTs and could not be studied. All patients received ATG induction therapy plus tacrolimus, mycophenolate and prednisolone. Glomerular filtration rate was measured before and 8 and 52 weeks after transplantation by serum clearance methods. Results: From week 8 to 52 after transplantation, mean fasting glucose decreased (SPK: 5.4 ± 0.7 to 5.1 ± 0.8 mmol/L, PTA: 5.4 ± 0.6 to 5.2 ± 0.7 mmol/L; both P < 0.05), and also 120-min post-OGTT glucose (SPK: 6.9 ± 2.9 to 5.7 ± 2.2 mmol/L; P = 0.07, PTA: 6.5 ± 1.7 to 5.7 ± 1.2 mmol/L; P < 0.05). Fasting C-peptide levels also decreased (SPK: 1500 ± 573 to 1078 ± 357 pmol/L, PTA: 1210 ± 487 to 1021 ± 434 pmol/L, both P < 0.005). Measured GFR decreased from enlistment to 8 weeks post transplant in PTA patients (94 ± 22 to 78 ± 19 mL/min/1.73 m2; P < 0.005), but did not deteriorate from week 8 to week 52 (SPK: 55.0 ± 15.1 vs 59.7 ± 11.3 ml/min/1.73 m2; P = 0.19, PTA: 76 ± 19 vs 77 ± 19 mL/min/1.73 m2; P = 0.74). Conclusion: Glycemic control and kidney function remain preserved in recipients with functioning SPK and PTA grafts 1 year after transplantation. [ABSTRACT FROM AUTHOR]

Background and Objective: Midazolam is the preferred clinical probe drug for assessing CYP3A activity. We have previously shown substantial intraindividual variability in midazolam absolute bioavailability and clearance in patients with obesity before and after weight loss induced by gastric bypass or a strict diet. The objective was to describe intraindividual variability in absolute bioavailability and clearance of midazolam in healthy individuals without obesity. Methods: This study included 33 healthy volunteers [28 ± 8 years, 21% males, body mass index (BMI) 23 ± 2.5 kg/m2] subjected to four pharmacokinetic investigations over a 2-month period (weeks 0, 2, 4, and 8). Semi-simultaneous oral (0 h) and intravenous (2 h later) midazolam dosing was used to assess absolute bioavailability and clearance of midazolam. Results: At baseline, mean absolute bioavailability and clearance were 46 ± 18% and 31 ± 10 L/h, respectively. The mean coefficient of variation (CV, %) for absolute bioavailability and clearance of midazolam was 26 ± 15% and 20 ± 10%, respectively. Approximately one-third had a CV > 30% for absolute bioavailability, while 13% had a CV > 30% for clearance. Conclusions: On average, intraindividual variability in absolute bioavailability and clearance of midazolam was low to moderate; however, especially absolute bioavailability showed considerable variability in a relatively large proportion of the individuals. [ABSTRACT FROM AUTHOR]

Background The aim of this study was to identify trends in total, deceased donor (DD) and living donor (LD) kidney transplantation (KT) rates in European countries. Methods The European Renal Association (ERA) Registry and the Global Observatory on Donation and Transplantation (GODT) databases were used to obtain the number of KTs in individual European countries between 2010 and 2018. General population counts were obtained from Eurostat or the national bureaus of statistics. The KT rate per million population (p.m.p.) and the average annual percentage change (APC) were calculated. Results The total KT rate in the 40 participating countries increased with 1.9% annually  [95%  confidence  interval  (CI) 1.5, 2.2] from 29.6 p.m.p. in 2010 to 34.7 p.m.p. in 2018, reflecting an increase of 3.4 p.m.p. in the DD-KT rate (from 21.6 p.m.p. to 25.0 p.m.p.; APC 1.9%; 95% CI 1.3, 2.4) and of 1.5 p.m.p. in the LD-KT rate (from 8.1 p.m.p. to 9.6 p.m.p.; APC 1.6%; 95% CI 1.0, 2.3). The trends in KT rate varied widely across European countries. An East–West gradient was observed for DD-KT rate, with Western European countries performing more KTs. In addition, most countries performed fewer LD-KTs. In 2018, Spain had the highest DD-KT rate (64.6 p.m.p.) and Turkey the highest LD-KT rate (37.0 p.m.p.). Conclusions The total KT rate increased due to a rise in the KT rate from DDs and to a lesser extent from LDs, with large differences between individual European countries. [ABSTRACT FROM AUTHOR]

Introduction: Rosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity. Methods: Patients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day). Results: A total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant. Conclusions: Neither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance. [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]

In combination with Bayesian estimates based on a population pharmacokinetic model, limited sampling strategies (LSS) may reduce the number of samples required for individual pharmacokinetic parameter estimations. Such strategies reduce the burden when assessing the area under the concentration versus time curves (AUC) in therapeutic drug monitoring. However, it is not uncommon for the actual sample time to deviate from the optimal one. In this work, we evaluate the robustness of parameter estimations to such deviations in an LSS. A previously developed 4-point LSS for estimation of serum iohexol clearance (i.e., dose/AUC) was used to exemplify the effect of sample time deviations. Two parallel strategies were used: (a) shifting the exact sampling time by an empirical amount of time for each of the four individual sample points, and (b) introducing a random error across all sample points. The investigated iohexol LSS appeared robust to deviations from optimal sample times, both across individual and multiple sample points. The proportion of individuals with a relative error greater than 15% (P15) was 5.3% in the reference run with optimally timed sampling, which increased to a maximum of 8.3% following the introduction of random error in sample time across all four time points. We propose to apply the present method for the validation of LSS developed for clinical use. [ABSTRACT FROM AUTHOR]

Background: There is scarce information on biopsy-verified kidney disease in childhood and its progression to chronic kidney disease stage 5 (CKD 5). This study aims to review biopsy findings in children, and to investigate risk of kidney replacement therapy (KRT). Methods: We conducted a retrospective long-term follow-up study of children included in the Norwegian Kidney Biopsy Registry (NKBR) and in the Norwegian Renal Registry (NRR) from 1988 to 2021. Results: In total, 575 children with a median (interquartile range, IQR) age of 10.7 (6.1 to 14.1) years were included, and median follow-up time (IQR) after kidney biopsy was 14.3 (range 8.9 to 21.6) years. The most common biopsy diagnoses were minimal change disease (MCD; n = 92), IgA vasculitis nephritis (IgAVN; n = 76), IgA nephropathy (n = 63), and focal and segmental glomerulosclerosis (FSGS; n = 47). In total, 118 (20.5%) of the biopsied children reached CKD 5, median (IQR) time to KRT 2.3 years (7 months to 8.4 years). Most frequently, nephronophthisis (NPHP; n = 16), FSGS (n = 30), IgA nephropathy (n = 9), and membranoproliferative glomerulonephritis (MPGN; n = 9) led to KRT. Conclusions: The risk of KRT after a kidney biopsy diagnosis is highly dependent on the diagnosis. None of the children with MCD commenced KRT, while 63.8% with FSGS and 100% with NPHP reached KRT. Combining data from kidney biopsy registries with registries on KRT allows for detailed information concerning the risk for later CKD 5 after biopsy-verified kidney disease in childhood. A higher resolution version of the Graphical abstract is available as Supplementary information [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]

Purpose: Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4β-hydroxycholesterol (4βOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4βOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods: The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4βOHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results: 4βOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (ρ = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (ρ = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (ρ = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (ρ = 0.15, p = 0.53). 4βOHC concentrations correlated weakly with midazolam absolute bioavailability (ρ = − 0.23, p = 0.027) and apparent oral clearance (ρ = 0.28, p = 0.008), but not with systemic clearance (ρ = − 0.03, p = 0.81). Conclusion: These findings suggest that 4βOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4βOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs. Trial registration: Clinical.Trials.gov identifier: NCT02386917. [ABSTRACT FROM AUTHOR]