High tacrolimus clearance – a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single‐center cohort study

Patients with high tacrolimus clearance are more likely to experience transient under‐immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (μg/l)] and changes in IFTA biopsy scores from week 7 to 1‐year post‐transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1‐year post‐transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of ≥2 at 1 year, odds ratio of 1.67 (95% CI; 1.11–2.51). In patients without fibrosis (ci + ct ≤ 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t ≤ 1 and ci + ct ≥ 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18–3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation.     

Long‐term risk for kidney donors with hypertension at donation – a retrospective cohort study

In the general population, small increases in blood pressure are associated with increased mortality. In kidney donors this association is less certain. We therefore assessed long‐term overall and cardiovascular mortality in donors who were hypertensive at the time of donation compared with normotensive donors. Hypertension was defined as blood pressure >140/90 mmHg or use of antihypertensive drugs. Adequate records available in 2131 donors revealed that 140 were hypertensive and 1991 were normotensive. Multivariable regression analyses were performed for overall and cardiovascular mortality. Hypertensive donors were significantly older (mean 57.7 vs. 46.9 years), more were males (44.3% vs. 41.5%), had higher body mass index (26.4 vs. 24.7) and lower estimated glomerular filtration rate (91.8 vs. 101.2 ml/min/1.73 m²). After a median observation time of 20.8 years (interquartile range 11) 71 hypertensive donors had died and 26 of the deaths were cardiovascular. Multivariable analysis did not suggest a generalizable association between hypertension and long‐term overall mortality [hazard ratio (HR) 1.1, 95% confidence interval (CI) 0.9–1.5, P = 0.34] or cardiovascular mortality (HR 1.1, 95% CI 0.7–1.8, P = 0.55). These data may support the use of older healthy kidney donors with hypertension at donation.     

Vitamin A deficiency impairs colonic healing but not adhesion formation in germ-free and conventional rats.

Vitamin A is well recognized as a factor of major importance in epithelial and connective tissue repair mechanisms. Recently it was shown that vitamin A deficiency caused overgrowth and translocation of intestinal bacteria in rats. The aim of this study was to investigate the healing of colonic anastomoses and formation of postsurgical adhesions in vitamin A-deficient germ-free and conventional rats. Fourteen germ-free and 10 conventional rats were allocated to four groups: germ-free rats not given vitamin A, germ-free rats given vitamin A, conventional rats not given vitamin A, and conventional rats given vitamin A. All rats underwent surgery for colonic anastomosis. Seven days afterward, they were euthanized, and the bursting pressure of colonic anastomosis and formation of peritoneal adhesions were evaluated. The bursting pressures in groups not given vitamin A were lower than in groups given vitamin A. The adhesion scores in germ-free groups were lower than in conventional groups. These findings demonstrated that vitamin A had an important role in healing of colonic anastomoses whether in the presence or absence of intestinal flora, and that intestinal bacteria had a greater effect than vitamin A on formation of postsurgical adhesions. This may suggest that the mechanism of healing of colonic anastomoses differs from that of postsurgical adhesion formation.     

Pre-emptive therapy of CMVpp65 antigen positive renal transplant recipients with oral ganciclovir: a randomized, comparative study.

BACKGROUND: About one-quarter of renal transplant patients will suffer from symptomatic cytomegalovirus (CMV) disease if no preventive therapeutic measures are taken. In this prospective, randomized single-centre study pre-emptive therapy with oral ganciclovir is compared with conventional deferred treatment. METHODS: Renal transplant recipients (n= 455) over 18 years of age were screened weekly for CMV pp65 antigenaemia during the first 12 weeks post-transplantation. If CMV pp65 antigen in leukocytes appeared within 8 weeks post-transplantation patients were randomized and included in the study. Five patients developed CMV disease before positive CMV pp65, and 14 patients with a positive antigen test developed CMV disease before randomization could take place, all these representing a limitation of the applicability of the results in the overall renal transplant population. Altogether 179 patients were not randomized for various reasons. Eighty patients completed the study, 42 were randomized to receive pre-emptive oral ganciclovir therapy and 38 to conventional deferred treatment (control group). RESULTS: Time from transplantation to start of ganciclovir capsules was 36 (12-60) days and duration of oral ganciclovir therapy was 49 (27-70) days, median (range). No patient in the pre-emptive treatment group, but nine of 38 patients (23.7%) in the control group, developed CMV disease during the first 12 weeks post-transplantation (P= 0.0009). In the period from 3 months to 1 year post-transplantation, two patients in each group developed CMV disease. There were no significant differences in acute rejection or renal function between treatment groups during the first post-transplant year. CONCLUSIONS: Pre-emptive oral ganciclovir therapy in renal transplant recipients during the first 12 weeks post-transplantation effectively prevents CMV disease during this time period. The incidence of late CMV disease (3 months to 1 year after transplantation) was similar in the two groups, indicating that pre-emptive therapy does not result in late onset of CMV disease.     

Short-chain fatty acids in intestinal content of germfree mice monocontaminated with Escherichia coli or Clostridium difficile

The short-chain fatty acids (SCFAs) have been analysed in coecal and small-intestinal content of conventional (CONV) and germfree (GF) mice, in germfree mice monocontaminated with Escherichia coli (MEC) or Clostridium difficile (MCD), and in germfree mice conventionalized by the visitor technique (EXG). The total concentrations of SCFAs in coecal content, measured by gas chromatography, were (mean (SD), mmol/kg): CONV, 125.2 (32.9); GF, 1.02 (0.39); MEC, 6.88 (0.76); MCD, 4.50 (0.12); and EXG, 115.6 (17.4). The concentrations of SCFAs were 3- to 25-fold higher in the coecum than in the small intestine in CONV, MEC, and EXG mice (p less than 0.05). The fermentation patterns (that is, the relative composition of the acids) of E. coli and Cl. difficile were distinctively different under defined in vitro conditions and similar to those found in intestinal content of monocontaminated animals. Combined gas chromatography and mass spectrometry showed that Cl. difficile produced an unusual metabolite, 2-methylbutyric acid, in vitro and in vivo. The findings indicate that the fermentation patterns are closely related to the bacteria. Variations in the bacterial flora may be more important in determining the concentrations and patterns of SCFAs in intestinal content than variations in the intake of substrate for SCFAs formation as dietary fibre.     

The metabolism of 4,8-DiMeIQx in conventional and germ-free rats

The aromatic amine mutagen, [^l4C]2-amino-3,4-8-trimethyl-imidazo[4,5-f]quinoxaline(4,8-DiMeIQx), which is derived from cooked food, was administeredto conventional and germ-free AGUS rats previously fed eithera semi-synthetic diet containing the cytochrome P-450 inducerß-naphtho-flavone (BNF) or a control diet withoutBNF. The germ-free animals had longer fecal transit times andlower induction of 7-ethoxyresorufin-O-deethylase activity thanconventional rats. Induction with BNF caused a greater percentageof the radioactivity to be excreted in the feces of both germ-freeand conventional rats. Feeding BNF also caused a 4-fold inductionin germ-free and a 24-fold induction in conventional rat intestinalenzyme levels. Analysis of the urinary and fecal metabolitesshowed no consistent differences between conventional and germ-freerats in the metabolite profile. Major metabolites were identifiedas 8-hydroxymethyl-DiMeIQx, N-acetyl-8-hydroxymethyl-DiMelQx,and 3-N-dimethyl-4-hydroxy-methyl-DiMelQx. The data from thisstudy indicate that intestinal microflora do not play a majorrole in the metabolism of 4,8-DiMeIQx, but the induction ofintestinal enzymes does affect the route and rate of excretion.     

Gut microflora associated characteristics in children with celiac disease

OBJECTIVES: The aim of the study was to investigate the metabolic function of intestinal microflora in children with celiac disease (CD) in order to find out if there is a deviant gut flora in CD patients compared to healthy controls. METHODS: The study group comprised children with CD, consecutively diagnosed according to current criteria given by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition. Thirty-six children were studied at presentation, i.e., on a normal gluten-containing diet, with clinical symptoms and signs indicative of CD, positive celiac serology markers, and a small bowel biopsy showing severe enteropathy. Forty-seven patients were studied when they had been on a gluten-free diet (GFD) for at least 3 months. For comparison, a group of 42 healthy controls (HC) were studied. The functional status of the intestinal microflora was evaluated by gas-liquid chromatography of short chain fatty acids (SCFAs) in fecal samples. RESULTS: There was a significant difference between untreated CD children and HC as well as between treated CD children and HC regarding acetic, i-butyric, i-valeric acid, and total SCFAs. The propionic and n-valeric acids differed significantly between CD children on GFD and HC. Moreover, there was a strong correlation between i-butyric and i-valeric acids in all study groups. CONCLUSIONS: This is the first study of the SCFA pattern in fecal samples from children with CD. The results indicate that there is a difference in the metabolic activity of intestinal microbial flora in children with CD compared to that in HC. The finding of a different pattern of some SCFAs in celiacs both at presentation and during treatment with GFD indicates that it is a genuine phenomenon of CD not affected by either the diet, the inflammation, or the autoimmune status of the patient.