304 Discussion In this study, we show that increasedurinary excretion of orally administered 52Cr-EDTA significantly correlates with elevated levels of fecal calprotectin in CD patients. Furthermore, CD patients with solely colonic disease activity show elevated 52Cr-EDTA/creatinine urinary excretion as opposed to CD patients having only an affected ileum. In addition, we observed an interesting trend of a negative association between 52Cr-EDTA-measured intestinal permeability and relative numbers of F. prausnitzii, whereas a trend of a positive associationwas observed between Enterobacteriaceae counts and urinary 52Cr-EDTA excretion. These correlations, though they lacked statistical significance, may suggest the possibility of a relationship between intestinal permeability and intestinal dysbiosis. Overall, our findings suggest that the measurement of urinary 52Cr-EDTA excretion might serve as novel approach for determining compromised intestinal permeability, as is characteristic for severe CD. Chromium-EDTA has been widely used as marker for intestinal permeability, due to its high sensitivity and the stability of the Cr-EDTA complex.35 However, most studies used the radioactive form 51Cr-EDTA that may have adverse effects due to radiation exposure. Here, we assessed the non-radioactive and inert 52Cr-EDTA to evaluate intestinal permeability in CD, in combination with quantifying urinary 52Cr by highly-sensitive ICP-MS. This method is particularly useful in detecting metal isotopes at very low concentrations in a safe, inexpensive and rigorously validated manner (Nexion 300X, Perkin Elmer, Medlon BV Enschede, The Netherlands). The currently applied ICP-MS method appeared to be highly sensitive in detecting 52Cr, with an internally determined lower limit of quantification (LLOQ) of 9.8 nmol/L. The average concentration of endogenous chrome in individuals in human blood and urine lies in the range of 0.1 - 0.5 μg/L (1.9 - 9.6 nmol/L), which falls below the LLOQ of ICP-MS and is thus negligibly small. For instance, the lowest individual value measured in our study cohort was 1352 nmol/L.48 This study assessed the 52Cr-EDTA intestinal permeability test in a relatively large study cohort of CD patients. Interestingly, the majority of these patients (70%) were in clinical remission according to the HBI, but still show a large variation in 52Cr-EDTA-measured intestinal permeability. Our study cohort is larger and less heterogeneous than all previous performed studies that have evaluated the potential application of Chromium-EDTA-measured intestinal permeability in IBD.11,12,25-33 Patient participation within our study was high, due to the non-invasive and nonradioactive nature of this test. However, careful test monitoring was required since several factors could affect urinary excretion levels of 52Cr-EDTA, such as adherence to the experimental protocol and the duration of urine collection.49 Also, in the present study cohort, no endoscopic disease activity data were available, which are preferentially used as representative of inflammatory disease activity in CD. Alternatively, we used the fecal calprotectin level as surrogate marker for CD disease activity.19,20,50-52 Here, fecal calprotectin levels were directly related to 52Cr-EDTA-measured intestinal permeability, which has previously not been established. Few studies specifically focused on the association between increased 51Cr-EDTAmeasured intestinal permeability and inflammatory disease activity.26,32,53 Hitherto, Berstad et al. found a significant correlation between 5-h urinary 51Cr-EDTA excretion and calprotectin levels in gut lavage fluid of IBD patients.53 Another study observed an association between increased Chapter 9
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