Hypomorphic expression of parathyroid Bmal1 disrupts the internal parathyroid circadian clock and increases parathyroid cell proliferation in response to uremia.

The molecular circadian clock is an evolutionary adaptation to anticipate recurring changes in the environment and to coordinate variations in activity, metabolism and hormone secretion. Parathyroid hyperplasia in uremia is a significant clinical challenge. Here, we examined changes in the transcriptome of the murine parathyroid gland over 24 hours and found a rhythmic expression of parathyroid signature genes, such as Casr, Vdr, Fgfr1 and Gcm2. Overall, 1455 genes corresponding to 6.9% of all expressed genes had significant circadian rhythmicity. Biological pathway analysis indicated that the circadian clock system is essential for the regulation of parathyroid cell function. To study this, a novel mouse strain with parathyroid gland-specific knockdown of the core clock gene Bmal1 (PTHcre;Bmal1flox/flox) was created. Dampening of the parathyroid circadian clock rhythmicity was found in these knockdown mice, resulting in abrogated rhythmicity of regulators of parathyroid cell proliferation such as Sp1, Mafb, Gcm2 and Gata3, indicating circadian clock regulation of these genes. Furthermore, the knockdown resulted in downregulation of genes involved in mitochondrial function and synthesis of ATP. When superimposed by uremia, these PTHcre;Bmal1flox/flox mice had an increased parathyroid cell proliferative response, compared to wild type mice. Thus, our findings indicate a role of the internal parathyroid circadian clock in the development of parathyroid gland hyperplasia in uremia.

Impact of extracorporeal blood flow rate on blood pressure, pulse rate and cardiac output during haemodialysis.

BACKGROUND: If blood pressure (BP) falls during haemodialysis (HD) [intradialytic hypotension (IDH)] a common clinical practice is to reduce the extracorporeal blood flow rate (EBFR). Consequently the efficacy of the HD (Kt/V) is reduced. However, only very limited knowledge on the effect of reducing EBFR on BP exists and data are conflicting. The aim of this study was to evaluate the effect and the potential mechanism(s) involved by investigating the impact of changes in EBFR on BP, pulse rate (PR) and cardiac output (CO) in HD patients with arteriovenous-fistulas (AV-fistulas). METHODS: We performed a randomized, crossover trial in 22 haemodynamically stable HD patients with AV-fistula. After a conventional HD session each patient was examined during EBFR of 200, 300 and 400 mL/min in random order. After 15 min when steady state was achieved CO, BP and PR were measured at each EFBR, respectively. RESULTS: Mean (SD) age was 71 (11) years. Systolic BP was significantly higher at an EBFR of 200 mL/min as compared with 300 mL/min [133 (23) versus 128 (24) mmHg; P < 0.05], but not as compared with 400 mL/min [133 (23) versus 130 (19) mmHg; P = 0.20]. At EBFR of 200, 300 and 400 mL/min diastolic BP, mean arterial pressure, PR and CO remained unchanged. CONCLUSION: Our study does not show any consistent trend in BP changes by a reduction in EBFR. Reduction in EBFR if BP falls during IDH is thus not supported. However, none of the patients experienced IDH. Further studies are required to evaluate the impact of changes in EBFR on BP during IDH.

[Novel hormones related to the calcium and phosphate homeostasis in kidney disease].

Calcium and phosphate levels are regulated by a complex interplay between parathyroid hormone (PTH), calcitriol, fibroblast growth factor 23 (FGF23) and its co-receptor αKlotho. Kidney failure causes severe disturbances in the mineral and bone homeostasis resulting in phosphate retention, hypocalcaemia and high plasma levels of FGF23 and PTH, and the patients develop fragile bones and vascular calcifications. Today's treatments aim to lower the levels of phosphate and PTH. Future studies need to clarify, if lowering the FGF23 level or supplementation with αKlotho will improve survival for patients with chronic kidney disease.