Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients.

AIM: In a cohort of 298 de-novo renal recipients treated with a standard tacrolimus loading dose of 0.2 mg/kg, the combined effects of the CYP3A5*1, POR*28, and CYP3A4*22 genotypes on early tacrolimus exposure (C0), dose requirements, and achievement of the therapeutic target, C0, were examined. The incidence of clinical events (e.g. acute rejection, diabetes mellitus) was compared between genotypes. RESULTS: Fast metabolizers (CYP3A5*1/POR*28T carriers) had two-fold to three-fold higher tacrolimus dose requirements compared with slow metabolizers (CYP3A5*3/*3/CYP3A4*22 carriers) and needed significantly more time to achieve the target tacrolimus C0 of a minimum 10 ng/ml (3.3±1.7 vs. 1.34±0.75 days; P<0.0001). No differences in acute rejection incidence and time to first rejection were observed. Slow metabolizers more frequently had tacrolimus C0 above the target range early after transplantation (70 vs. 13% on day 3); however, this did not translate into a higher incidence of post-transplantation diabetes mellitus or graft dysfunction. Multivariate analyses identified the CYP3A5*1/POR*28/CYP3A4*22 genotype combination as the single strongest determinant of tacrolimus dose requirements throughout the first year, explaining between 24-40% of its variability, whereas recipient age, hematocrit, and delayed graft function were additional nongenetic determinants of tacrolimus dose. CONCLUSION: Combining the CYP3A5*1, POR*28 and CYP3A4*22 genotypes allows partial differentiation of early tacrolimus dose requirements and the time to reach therapeutic target concentrations after transplantation, but without obvious clinical implications. Larger prospective studies need to address the clinical relevance of early combined genotype-based tacrolimus dosing in de-novo renal recipients.

Development of pouchitis following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis: A role for serological markers and microbial pattern recognition receptor genes.

BACKGROUND AND AIMS: Pouchitis, the most common complication after proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, has been attributed to altered composition of faecal flora. We investigated the role of antimicrobial and antiglycan antibodies and polymorphisms in microbial pattern recognition receptor genes. METHODS: Clinical charts of all 184 patients with ulcerative colitis who underwent IPAA between 1990-2004 were reviewed for pre- and post-operative disease course. RESULTS: Follow-up data were available in 172 patients [67 female, median age at proctocolectomy 39.1 years]. During a median follow-up of 6.7 (interquartile range 3.7-10.5) years, 80 patients (47%) developed at least one episode of pouchitis. Cox proportional-hazard regression identified extra-intestinal manifestations [HR 1.78 (95%CI 1.10-2.88), p=0.020], a GT/TT genotype at Toll-like-receptor-1 S87I [HR 1.64 (1.01-2.66), p=0.047], anti-chitobioside carbohydrate antibodies [HR 2.03 (1.11-3.70), p=0.021] and young age at diagnosis [p=0.003] to be independently associated with pouchitis. Factors associated with chronic pouchitis, diagnosed in 33 patients (19%), were extra-intestinal manifestations [HR 2.45 (1.07-5.62), p=0.034], backwash ileitis [HR 3.15 (1.10-9.00), p=0.032], outer-membrane porin antibodies [HR 2.67 (1.20-5.94), p=0.016] and young age at proctocolectomy [p=0.008]. CONCLUSIONS: : The reported association with antibodies and Toll-like-receptor-1 supports the pathophysiological role of the faecal flora in the development of pouchitis.

Influence of long-term administration of lactulose and Saccharomyces boulardii on the colonic generation of phenolic compounds in healthy human subjects.

OBJECTIVE: Proteins are degraded in the colon by bacterial fermentation into potentially toxic metabolites such as phenolic compounds. The aim of the present study was to investigate whether long-term administration of lactulose or Saccharomyces boulardii cells would result in a lower protein degradation. In addition, the influence of a long-term dietary intake on different gastrointestinal parameters was investigated. METHODS: The effect of long-term intervention of the substrates was evaluated in a randomized, cross-over study in 43 healthy volunteers. At the start of the study and at the end of each 4-week treatment period, urine was collected during 48 h in different fractions and faeces during 72 h. Breath test samples and blood samples were taken to study gastrointestinal parameters. RESULTS: No influence of long-term administration of both substrates was found on GE, OCTT and serum lipids. A significant decrease in small intestinal permeability was found after long-term dietary intervention with lactulose. Long-term administration of lactulose significantly decreased urinary p-cresol excretion, but did not lower fecal p-cresol excretion. No significant effects were observed after S. boulardii intake. CONCLUSION: The results obtained in present study have indicated that colonic amino acid fermentation can be reduced by the administration of lactulose as a fermentable carbohydrate.