Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers

Aims: The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Methods: Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3mg of powder obtained from oral capsules was applied under the tongue for a period of 15min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15mg of the oral powder was used. Oral administration consisted of 7mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Results: Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Conclusions: Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered

mHealth-based experience sampling method to identify fatigue in the context of daily life in haemodialysis patients

Background: Fatigue in haemodialysis (HD) patients is a prevalent but complex symptom impacted by biological, behavioural, psychological and social variables. Conventional retrospective fatigue questionnaires cannot provide detailed insights into symptom variability in daily life and related factors. The experience sampling methodology (ESM) overcomes these limitations through repeated momentary assessments in patients' natural environments using digital questionnaires. This study aimed to gain in-depth understanding of HD patients' diurnal fatigue patterns and related variables using a mobile Health (mHealth) ESM application and sought to better understand the nature of their interrelationships.Methods: Forty HD patients used the mHealth ESM application for 7days to assess momentary fatigue and potentially related variables, including daily activities, self-reported physical activity, social company, location and mood.Results: Multilevel regression analyses of momentary observations (n=1777) revealed that fatigue varied between and within individuals. Fatigue was significantly related to HD treatment days, type of daily activity, mood and sleep quality. Time-lagged analyses showed that HD predicted higher fatigue scores at a later time point (beta =0.22, P=0.013). Interestingly, higher momentary fatigue also significantly predicted more depressed feelings at a later time point (beta =0.05, P=0.019) but not the other way around.Conclusions: ESM offers novel insights into fatigue in chronic HD patients by capturing informative symptom variability in the flow of daily life. Electronic ESM as a clinical application may help us better understand fatigue in HD patients by providing personalized information about its course and relationship with other variables in daily life, paving the way towards personalized interventions

Unraveling Fatigue in Hemodialysis Patients:comparing retrospective reports to real-time assessments with an mHealth Experienced Sampling Method

Context. Fatigue is prevalent among hemodialysis (HD) patients and associated with depressive mood. To advance our understanding of its etiology and develop appropriate treatments, reliable measurement instruments are needed. However, conventional fatigue and mood questionnaires are prone to bias because of their retrospective nature and may misrepresent or overestimate actual symptom experience (i.e., the so-called memory-experience gap). Experience sampling methodology (ESM) overcomes this limitation through repeated real-time assessments in patients' natural environment, thereby providing reliable and ecologically valid data.Objectives. We investigated to what extent retrospective symptom reporting accurately represents real-time experiences of fatigue and mood in HD patients using an ESM mobile Health application (PsyMate (TM); smartHealth GmbH, Luxembourg).Methods. Forty HD patients used the PsyMate for one week to assess real-time fatigue and mood. In addition, they retrospectively evaluated their symptom experience completing end-of-day and end-of-week questionnaires as well as the conventional Fatigue Severity Scale and Hospital Anxiety and Depression Scale.Results. Results of real-time observations (N = 1777) showed that fatigue and mood varied between and within individuals. Retrospective end-of-week fatigue evaluation was significantly higher than the average real-time fatigue score; t(38) = 3.54, P = 0.001, and d = 0.57. Fatigue Severity Scale and Hospital Anxiety and Depression Scale correlated moderately to strong with the average ESM score for fatigue and mood: r = 0.66 and r = 0.77, respectively.Conclusion. Retrospective fatigue assessment may lead to overestimation of real-time symptom experience. ESM provides detailed insight and personalized information about symptom experiences, which may be crucial for the design of more targeted and personalized interventions for fatigue and mood problems in HD patients. (C) 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved

Granulomatous interstitial nephritis and Crohn's disease

Granulomatous interstitial nephritis has been observed in <1% of native renal biopsies. Here, we describe two patients with granulomatous interstitial nephritis in relation to Crohn's disease. Circulating helper and cytotoxic T cells were highly activated, and both cell types predominated in the interstitial infiltrate, indicating a cellular autoimmune response. After immunosuppressive treatment, renal function either improved or stabilized in both patients. In conclusion, granulomatous interstitial nephritis is a genuine extraintestinal manifestation of Crohn's disease, the treatment of which should include immunosuppressive agents

Advanced glycation endproducts and dicarbonyls in end-stage renal disease:associations with uraemia and courses following renal replacement therapy

Background. End-stage renal disease (ESRD) is strongly associated with cardiovascular disease (CVD) risk. Advanced glycation endproducts (AGEs) and dicarbonyls, major precursors of AGEs, may contribute to the pathophysiology of CVD in ESRD. However, detailed data on the courses of AGEs and dicarbonyls during the transition of ESRD patients to renal replacement therapy are lacking. Methods. We quantified an extensive panel of free and protein-bound serum AGEs [N-is an element of-(carboxymethyl)lysine (CML), N-is an element of-(carboxyethyl)lysine (CEL), N-delta-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)], serum dicarbonyls [glyoxal (GO), methylglyoxal (MGO), 3-deoxyglucosone (3-DG)] and tissue AGE accumulation [estimated by skin autofluorescence (SAF)] in a combined cross-sectional and longitudinal observational study of patients with ESRD transitioning to dialysis or kidney transplantation (KTx), prevalent dialysis patients and healthy controls. Cross-sectional comparisons were performed with linear regression analyses, and courses following renal replacement therapy were analysed with linear mixed models. Results. Free and protein-bound AGEs, dicarbonyls and SAF were higher in chronic kidney disease (CKD) Stage 5 non-dialysis (CKD 5-ND; n = 52) and CKD Stage 5 dialysis (CKD 5-D; n = 35) than in controls (n = 42). In addition, free AGEs, protein-bound CML, GO and SAF were even higher in CKD 5-D than in CKD5-ND. Similarly, following dialysis initiation (n = 43) free and protein-bound AGEs, and GO increased, whereas SAF remained similar. In contrast, following KTx (n = 21), free and protein-bound AGEs and dicarbonyls, but not SAF, markedly declined. Conclusions. AGEs and dicarbonyls accumulate in uraemia, which is even exaggerated by dialysis initiation. In contrast, KTx markedly reduces AGEs and dicarbonyls. Given their associations with CVD risk in high-risk populations, lowering AGE and dicarbonyl levels may be valuable