MO026TREATMENT WITH ACTIVE VITAMIN D DOES NOT IMPROVE LEFT VENTRICULAR HYPERTROPHY BUT FURTHER INCREASES FGF23 AND ACCELERATES CKD PROGRESSION IN CHILDREN
Authors: Leifheit-Nestler Maren , Schoen Anne , Deppe Jennifer , Karabay Bayazit Aysun , Obrycki Łukasz , Canpolat Nur , Kaplan Bulut Ipek , Azukaitis Karolis , Stangl Gabriele , Behnisch Rouven , Shroff Rukshana , Bacchetta Justine , Querfeld Uwe , Schaefer Franz , Haffner Dieter 
Published: June 2020

Abstract

Background and Aims
Elevated FGF23, activation of the renin-angiotensin-aldosterone system (RAAS), and vitamin D and Klotho deficiency promote left ventricular hypertrophy (LVH) and LV fibrosis in chronic kidney disease (CKD). Whether treatment with active vitamin D affects uremic cardiomyopathy and/or FGF23/Klotho system in CKD is unclear.

Method
5/6 nephrectomized (5/6Nx) rats, as a well-established model of CKD, were dose-dependently treated with calcitriol for 10 weeks and the cardiac phenotype, including local RAAS activation, was investigated compared to untreated 5/6Nx and sham-operated rats. Additionally, 38 children with eGFR ≤ 30 ml/min/1.73 m2 selected from the Cardiovascular Comorbidity in Children with CKD (4C) study were enrolled in a case-control study. Nineteen children were started on active vitamin D treatment with either calcitriol or calcidiol (average dosage 0.4 μg/day), and 19 CKD children with non-active vitamin D treatment matched for age, eGFR, serum calcium, parathyroid hormone, and phosphate served as controls. LV mass index (LVMI), LVH prevalence (LVMI &gt;95th percentile), intact (iFGF23) and C-terminal FGF23 (cFGF23), and soluble Klotho (sKlotho) were assessed at baseline and after nine months.

Results
In 5/6Nx rats, FGF23 synthesis in bone and heart was enhanced compared to sham-operated rats, and calcitriol further stimulated its expression in bone only. Renal Klotho expression was reduced in 5/6 rats and almost normalized after calcitriol treatment. 5/6Nx induced cardiomyocyte growth and LV fibrosis, and calcitriol treatment significantly ameliorated both. Cardiac RAAS genes, such as angiotensinogen, renin, angiotensin-converting-enzyme, and angiotensin II receptor type I, were significantly upregulated in 5/6Nx rats compared to sham-operated animals, and normalized by calcitriol treatment.
In the 4C study cohort, median plasma cFGF23 and iFGF23 were significantly elevated in both groups, whereas sKlotho was not altered compared to healthy children. Forty-seven percent and 42% of active vitamin D-treated patients and controls, respectively, received blood pressure (BP) medications, however diastolic BP was slightly but significantly enhanced in both groups compared to healthy children. Mean LVMI and LVH prevalence of 47% in active vitamin D-treated patients and controls did not differ at baseline. After nine months, median cFGF23 and iFGF23 were significantly increased in active vitamin D-treated patients compared to controls. sKlotho levels were decreased in the active vitamin D-treated group compared to baseline but not in controls. A significant decline in median eGFR was observed in active vitamin D group but not in controls. Likewise, the median eGFR change during the observation period was higher in the active vitamin D group compared to controls. Median LVMI as well as frequency of LVH did not change significantly during vitamin D treatment, nor in controls. Consequently, final median LVMI as well as percentage of patients with LVH did not significantly differ between groups.

Conclusion
Calcitriol treatment in 5/6Nx rats improves cardiac hypertrophy and fibrosis, reduces uremia-induced cardiac RAAS gene expression, and improves renal Klotho expression. By contrast, treatment with active vitamin D does not decrease the prevalence of LVH in children with advanced CKD compared to matched controls. This may be due to further enhancement of FGF23 levels, faster progression of CKD associated with reduced Klotho in active vitamin D-treated patients and/or concomitant treatment with RAAS inhibitors. The latter may blunt the favorable effects of calcitriol on the activated RAAS.