Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism.
Renal α-Klotho (α-KL) plays a fundamental role as a co-receptor for fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 vitamin D3 (1,25VitD3). Disruption of FGF23-α-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal α-KL expression and a reciprocal rise in serum FGF23. It remains unclear, however, whether the rise in FGF23 is related to the loss of renal α-KL. We evaluated α-KL expression in renal biopsy samples and measured levels of several parameters of mineral metabolism, as well as soluble α-KL (sKL), in serum and urinary samples from CKD patients (n = 236). We found that although renal α-KL levels were significantly reduced and serum FGF23 levels were significantly elevated in early and intermediate CKD, serum phosphate levels remained within the normal range. Multiple regression analysis showed that the increases in FGF23 were significantly associated with reduced renal function and elevated serum phosphate, but were not associated with loss of renal α-KL. Moreover, despite falling renal α-KL levels, the increase in FGF23 enhanced urinary fractional excretion of phosphate and reduced serum 1,25VitD3 levels in early and intermediate CKD, though not in advanced CKD. Serum sKL levels also fell significantly over the course of CKD, and renal α-KL was a significant independent determinant of sKL. These results demonstrate that FGF23 levels rise to compensate for renal failure-related phosphate retention in early and intermediate CKD. This enables FGF23-α-KL signaling and a neutral phosphate balance to be maintained despite the reduction in α-KL. In advanced CKD, however, renal α-KL declines further. This disrupts FGF23 signaling, and serum phosphate levels significantly increase, stimulating greater FGF23 secretion. Our results also suggest the serum sKL concentration may be a useful marker of renal α-KL expression levels.
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Hirokazu
H
Sakan
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan ; Department of Pathology, Nara Medical University, Kashihara, Nara, Japan.
Kimihiko
K
Nakatani
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Osamu
O
Asai
Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Akihiro
A
Imura
Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Tomohiro
T
Tanaka
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Shuhei
S
Yoshimoto
Department of Urology, Tojinkai Hospital, Kyoto, Japan.
Noriyuki
N
Iwamoto
Departments of Community Health and Epidemiology, Nara Medical University, Kashihara, Nara, Japan.
Norio
N
Kurumatani
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan ; Division of Nephrology, Department of General Medicine, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui, Japan.
Masayuki
M
Iwano
Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yo-Ichi
Y
Nabeshima
Department of Pathology, Nara Medical University, Kashihara, Nara, Japan.
Noboru
N
Konishi
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan ; Department of Regulatory Medicine for Blood Pressure, Nara Medical University, Kashihara, Nara, Japan.
Yoshihiko
Y
Saito
D000328:Adult; D000368:Aged; D002117:Calcitriol / Q000097:blood*; D018450:Disease Progression; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D015870:Gene Expression; D005919:Glomerular Filtration Rate; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D000090265:Klotho Proteins; D008297:Male; D008875:Middle Aged; D010710:Phosphates / Q000097:blood* / Q000652:urine; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C000717427:FGF23 protein, human; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol