Renal effects of fibroblast growth factor 23 infusions.

Londen, M. van (Marco) (2013) Renal effects of fibroblast growth factor 23 infusions. thesis, Medicine.

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Abstract

Chronic kidney disease (CKD) is a serious health burden, affecting millions of people throughout the world. Patients with CKD can have progression to renal replacement dependent end-stage renal disease and have an increased risk of cardiovascular mortality. Epidemiological studies suggested an association between deregulated phosphate homeostasis, characterized by high fibroblast growth factor 23 (FGF23) levels, and progression of renal function loss in CKD. However, whether FGF23 causes renal damage has not yet been studied. We performed a pilot study to test the feasibility and efficacy of recombinant FGF23 (rFGF23) infusion by osmotic minipumps in mice. To address this, healthy C57BL/6 mice underwent different treatment regimens (n=5 per group): rFGF23 via osmotic minipumps located in the peritoneal cavity at different doses (1, 2 or 4µg/kg/hr), minipumps with vehicle (PBS), or i.p. rFGF23 injections (40µg/kg, twice daily). Animals were sacrificed, and blood and kidneys were collected after 7 days of treatment. To test the efficacy and physiological effects of rFGF23 infusion, we measured plasma FGF23 levels, several other circulating parameters of calcium/phosphorus metabolism, and renal expression of the FGF23 co-receptor klotho, and vitamin D-related enzymes 1-alpha hydroxylase and 24-hydroxylase. To investigate the effects of rFGF23 on the kidney, we determined markers of renal function (plasma and urine urea and creatinine) and renal expression of the prefibrotic marker alpha-smooth muscle actin (α-SMA). The mice receiving FGF23 through minipump infusion showed a dose-dependent increase in plasma FGF23 levels (median: 6592.18 vs 1250.82 vs 4021.52 pg/ml, vs 237.15 in vehicle group, p for trend<0.05). Also animals that received rFGF23 by i.p. injections displayed increased plasma FGF23 levels compared with vehicle controls (median: 2989.21 vs 237.15, p<0.05). However in all mice that received rFGF23, plasma and urinary phosphate levels were similar to vehicle mice. Mice that had received rFGF23 by i.p. injections showed reduced expression of the vitamin D-deactivating enzyme 24-hydroxylase. On the other hand, mice treated with rFGF23 by minipumps displayed no change in renal vitamin D enzyme expression compared to controls, but they did show a dose-dependent reduction in renal klotho expression. None of the groups treated with rFGF23 showed any difference in renal α-SMA expression, compared to vehicle controls. We conclude that, although rFGF23 infusion by i.p. osmotic minipumps in mice led to strongly increased plasma FGF23 levels, the expected physiological effects were lacking. Possible explanations include underdosage of rFGF23, the presence of relatively high concentrations of bovine serum albumin (BSA) in the recombinant FGF23 solution that was infused, and compensatory mechanisms in the mice. We propose an additional pilot study with a higher dose of non-BSA-containing rFGF23 to further address the effects of rFGF23 in mice.

Item Type:	Thesis (Thesis)
Supervisor name:	Mirkovic, Drs. K. and Borst, Dr. M.H. de and Navis, Prof. dr. G.J.
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 11:07
Last Modified:	25 Jun 2020 11:07
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/2649

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