Phosphate and klotho

Professor Makoto Kuro-o, USA

The klotho gene encodes a single trans-membrane protein that is predominantly expressed in the kidney, specifically the distal convoluted tubule (DCT), as well as the parathyroid glands, the pituitary, hypothalamus, testes, ovaries and pancreatic β cells; it is associated with endocrine organs. Secretion of klotho is stimulated by low extracellular calcium and phosphate.


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Figure 8: CKD is a state of klotho deficiency.
Figure 8: CKD is a state of klotho deficiency.

Klotho is an obligate co-receptor for FGF-23, and the phenotype of klotho knockout mice is very similar to that of FGF-23 knockout mice, with both phenotypes having defects associated with advanced aging and disordered mineral metabolism.

In klotho knockout mice, a low phosphate diet rescues the animals from many of the features of premature aging and reduces hyperphosphatemia; however, it has no effect on hypercalcemia or low levels of vitamin D observed in these animals.

The concept that CKD could be viewed as a state of accelerated aging associated with klotho deficiency and phosphate retention was discussed. As CKD progresses, klotho decreases in the serum and urine, reaching almost zero in CKD stage 5 (Figure 8).

These changes start to occur very early in the course of CKD and result in changes to FGF-23, vitamin D and parathyroid hormone. A decrease in klotho results in an increase in FGF- 23 to try to compensate; this leads to lower levels of calcitriol and higher levels of parathyroid hormone (leading to an increase in FGF-23). The various treatments for CKD need to break this vicious cycle.

As CKD progresses, klotho decreases in the serum and urine, reaching almost zero in CKD stage 5

Klotho exists in two forms: membrane bound and clipped/secreted. The membrane form of klotho must be expressed to mediate the effects of FGF-23. Secreted klotho has been detected in the blood, urine and CSF, and activates calcium channels in the DCT, promoting renal calcium reabsorption, resulting in FGF-23 lowering serum phosphate but not calcium. Secreted klotho acts independently of FGF-23, appears to regulate the function of various ion channels and transporters, including phosphate transporters, and can induce phosphaturia, possibly through the inactivation of sodium/phosphate co-transporters in the PT.

In animals, secreted klotho in blood is a biomarker for decreased expression in the kidney; this has yet to be confirmed in humans. Secreted klotho can inhibit Pit 1 and 2 in multiple organs, and can also affect the signalling pathways of TGF-β and IGF-1. Its effects on hydroxylase are unknown, and it is not thought to mediate the phosphaturic effects of FGF-23. It is believed that secreted klotho acts as a paracrine factor within the kidney, acting from DCT to neighboring PT, but not in the general circulation.


Worldwide vitamin D deficiency: science or fashion

Dr. Roger Bouillon, Belgium

Dr. Bouillon shared data and information on the importance of vitamin D. 1,25-dihydroxyvitamin D (1,25(OH)2D) and the vitamin D receptor (VDR) (1,25-(OH)2D-VDR) interact directly on the parathyroid glands, kidney, GI tract and bone, and indirectly through its effects on FGF-23, to maintain phosphate and calcium levels in the blood (Figure 9).

A number of studies have been conducted to investigate the optimal threshold level of vitamin D for bone health. It has been shown that the risk of SHPT is reduced with serum 25-OH-D levels ≥20 ng/mL, and supplementation with >400– 800 IU vitamin D3/day decreases risk of fractures and falls by ~20%, according to the results from 12 meta-analyses and 10–20 randomized clinical trials. It was concluded, therefore, that 25-OH-D >20 ng/ mL will safely eliminate most of the potential extra-skeletal risks of vitamin D deficiency.

Figure 9: Scheme of interaction between 1,25-(OH)2D-VDR system and phosphate homeostasis.
Figure 9: Scheme of interaction between 1,25-(OH)2D-VDR system and            phosphate homeostasis.

In order to respond to the worldwide epidemic of vitamin D deficiency and insufficiency, one of three strategies could be employed: (1) wait for better evidence-based studies; (2) provide vitamin D supplements (800 IU/day) for all adults and especially those in at-risk groups to eliminate most extra-skeletal disease risks due to vitamin D deficiency; and (3) recommend better vitamin D status (>32 or >40 ng/mL) for all adults either by higher exposure to UV-B sunlight or by a vitamin D intake of 2000-4000 IU/day.

Questions raised included the safety of 2000 IU vitamin D/day, as there are no data from RCTs to date, and the possibility of recommending a target of 30 ng/mL. An RCT investigating 30-40 ng/mL serum levels needs to be conducted in patients with CKD to investigate its safety and efficacy.

It was also noted that, as vitamin D is stored in fat, obese individuals need more vitamin D than lean individuals.

It was suggested that everyone over 65 years of age should receive 1 g calcium and 800 mg vitamin D daily, although there are no data currently available for younger adults or adolescents. The Institute of Medicine will announce its decision regarding vitamin D supplementation in the USA at a later date.


Bone, from a reservoir of minerals to a regulator of energy expenditure

Dr. Cyrille Confavreux, France

Bone, appetite, and reproduction are thought to be regulated by a neuroendocrine connection via a common hormonal system in the brain; leptin (an adipocyte hormone produced by the fat cells of the body) regulates appetite and reproduction, and controls bone mass indirectly. Leptin deficient mice (Ob/Ob) are obese and sterile, and have increased bone mass, which can be returned to normal by intracerebroventricular infusion of leptin.

Figure 10: Fat controls bone mass — but does bone regulate energy metabolism?
Figure 10: Fat controls bone mass — but does bone regulate energy metabolism?

Serotonin is a candidate neuromediator for leptin activity, and antiserotoninergic antidepressants increase patients’ appetite, which supports the use of serotonin as an appetite regulator.

Studies have shown that the sympathetic nervous system (SNS), via beta2-adrenergic receptor, mediates leptin inhibition of bone formation (Figure 10). If leptin controls bone mass, is this action reciprocated by the bone controlling metabolism?

Osteocalcin, an osteoblast-secreted hormone, regulates insulin and adiponectin expression and, consequently, metabolism.

Questions following this presentation included the suggestion that obese people have increased bone mass, and the need to investigate further the direct effects of leptin on bone and mineral metabolism, eg, stimulating FGF-23 and reducing 1,25(OH)D; it is possible that leptin’s direct effects on bone are stimulatory where whereas its neuroendocrine effects are inhibitory.