Abstract Background and Aims Patients with end-stage kidney disease (ESKD) are known to have higher plasma concentrations of metabolic waste products than healthy individuals. Patients with Primary Hyperoxaluria (PH), a rare congenital cause of ESKD, suffer from hepatic overproduction of the metabolic end product oxalate. Plasma oxalate (POx) levels are determined in the diagnostic and therapeutic work-up for PH. Remarkably, correct interpretation of these values is hampered by the absence of knowledge concerning POx levels in patients with ESKD due to common causes. Method In this observational study, we obtained POx values in patients with ESKD due to another cause than PH, to establish reference values in this patient group. We collected blood samples from 120 adults with eGFR < 15 mL/min/1.73 m2 who required maintenance hemodialysis or peritoneal dialysis at the Amsterdam UMC. Results While there was a wide variation in POx levels in patients with ESKD, the median was 50 umol/L and lowest values were twice the upper reference limit that applies to healthy individuals (6.7 umol/L). Conclusion This study shows that POx levels of 50 umol/L are not necessarily suggestive for PH which contradicts the current literature. This study could lead to a paradigm shift in the diagnostic and therapeutic work-up for patients with ESKD.

Recently, it was suggested that β-aminoisobutyric acid (BAIBA) is a myokine involved in browning of fat. However, there is no evidence for an acute effect of exercise supporting this statement and the metabolic distinct enantiomers of BAIBA were not taken into account. Concerning these enantiomers, there is at this point no consensus about resting concentrations of plasma R- and S-BAIBA. Additionally, a polymorphism of the alanine - glyoxylate aminotransferase 2 (AGXT2) gene (rs37369) is known to have a high impact on baseline levels of total BAIBA, but the effect on the enantiomers is unknown. Fifteen healthy recreationally active subjects, with different genotypes of rs37369, participated in a randomized crossover trial where they exercised for 1 h at 40% of Ppeak or remained at rest. Plasma samples were analyzed for R- and S-BAIBA using dual column HPLC-fluorescence. The plasma concentration of baseline R-BAIBA was 67 times higher compared to S-BAIBA (1734 ± 821 vs. 29.3 ± 7.8 nM). Exercise induced a 13 and 20% increase in R-BAIBA and S-BAIBA, respectively. The AGXT2 rs37369 genotype strongly affected baseline levels of R-BAIBA, but did not have an impact on baseline S-BAIBA. We demonstrate that BAIBA should not be treated as one molecule, given (1) the markedly uneven distribution of its enantiomers in human plasma favoring R-BAIBA, and (2) their different metabolic source, as evidenced by the AGXT2 polymorphism only affecting R-BAIBA. The proposed function in organ cross talk is supported by the current data and may apply to both enantiomers, but the tissue of origin remains unclear.

Bile acids (BAs) are molecules with endocrine activities controlling several physiological functions such as immunity, glucose homeostasis, testicular physiology and male fertility. The role of the nuclear BA receptor FXRα in the control of BA homeostasis has been well characterized. The present study shows that testis synthetize BAs. We demonstrate that mice invalidated for the gene encoding FXRα have altered BA homeostasis in both liver and testis. In the absence of FXRα, BA exposure differently alters hepatic and testicular expression of genes involved in BA synthesis. Interestingly, Fxrα-/- males fed a diet supplemented with BAs show alterations of testicular physiology and sperm production. This phenotype was correlated with the altered testicular BA homeostasis and the production of intermediate metabolites of BAs which led to the modulation of CAR signaling pathways within the testis. The role of the CAR signaling pathways within testis was validated using specific CAR agonist (TCPOBOP) and inverse agonist (androstanol) that respectively inhibited or reproduced the phenotype observed in Fxrα-/- males fed BA-diet. These data open interesting perspectives to better define how BA homeostasis contributes to physiological or pathophysiological conditions via the modulation of CAR activity.