PRESENTED BY
MAKOTO KURO-O

Presentation Summary

Written by: Miljan Krčobić
Reviewed by: Jasna Trbojević-Stanković, Milica Maksimović and Makoto Kuro-o

Klotho, the Greek goddess who spins the thread of life, has become popular among nephrologists, as the genes named after her encode co-receptors for hormones that play critical roles in the pathophysiology of chronic kidney disease (CKD) [1].

The Klotho gene was discovered in 1997 when mice with serendipitous silencing of this gene developed premature ageing syndrome [1]. The Klotho proteins (αKlotho and βKlotho) are essential components of endocrine fibroblast growth factor receptor (FGFR) complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGFRs. Alpha-Klotho is predominantly expressed in the distal convoluted tubules of the kidneys whereas βKlotho is located in fat tissue and the liver [2].

The FGF23-αKlotho endocrine axis in CKD

FGF23 is a bone-derived phosphaturic hormone that binds to the αKlotho-FGFR complex to increase phosphate excretion per nephron. To maintain phosphate balance, patients with CKD compensate for the decrease in the nephron number with a rise in FGF23 levels, which increases phosphate excretion per nephron. The rise in FGF23 is followed by a decrease in active vitamin D and an increase in parathyroid hormone (PTH), leading to the disorder known as CKD-mineral-bone disorder (CKD-MBD), one of the major risk factors for cardiovascular complications. Serum inorganic phosphate levels are the last to increase resulting in hyperphosphataemia. Additionally, elevated PTH levels further increase FGF23 levels. This positive feedback loop continues to enhance an increase in FGF23 levels. Both the increase in FGF23 levels and the decrease in active vitamin D levels can suppress αKlotho expression, potentially resulting in FGF23 resistance and a loss of the renoprotective properties of αKlotho (Figure 1) [3].

Figure 1: The FGF23–αKlotho endocrine axis [3]

The FGF21-βKlotho endocrine axis in CKD

FGF21 is a hormone secreted from hepatocytes in response to various types of stress, such as fasting and inflammation. It binds to the βKlotho–FGFR1c complex and induces metabolic responses to fasting (i.e. lipolysis in adypocytes). FGF21 also crosses the blood-brain barrier and binds to βKlotho expressed in the suprachiasmatic nucleus activating the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis [3]. Furthermore, FGF21 was reported to extend lifespan when overexpressed in mice, suggesting that the FGF–Klotho endocrine system has an effect on ageing processes [4].

Similarly to FGF23, serum levels of FGF21 also increase in patients with CKD, as early as in stage 2, and continue to rise as renal function declines. In dialysis patients, high FGF21 predicts high mortality. The osteopenia in FGF21-overexpressing transgenic mice is associated with decreased osteoblastogenesis and increased adipogenesis in the bone marrow, which may potentially contribute to the pathophysiology of CKD–MBD. Increased levels of FGF21 may also cause circadian rhythm disturbance, daily blood pressure fluctuations and depression. These symptoms are often seen in CKD patients [3].

The FGF19-βKlotho endocrine axis in CKD

FGF19 is a satiety hormone secreted by intestinal epithelial cells in response to primary bile acids (bile acids released from the liver) and secondary bile acids (primary bile acid metabolites produced by intestinal bacteria). FGF19 binds to the βKlotho–FGFR4 complex that is present on hepatocytes to suppress the expression of CYP7A1-gene, which encodes the rate-limiting enzyme of bile acid synthesis, cholesterol 7α-hydroxylase. Thus, the FGF19–βKlotho endocrine axis potentially affects the composition of the microbiome and vice versa. Although the connection between the FGF19–βKlotho endocrine axis and CKD is poorly understood, patients with CKD frequently show microbial imbalance in the gut and a blunted postprandial FGF19 response [3, 5].

Theory of calciprotein particles (CPPs) as a pathogen

When nephron number is decreased and FGF23 levels are increased in the context of CKD and ageing, the postprandial increase in serum inorganic phosphate levels is likely to be enhanced and prolonged. This rise in serum inorganic phosphate can potentially lead to the formation of calciprotein particles (CPPs), which are colloids comprised of deposits of calcium phosphate adsorbed onto serum protein fetuin A. CPPs can induce immune cell activation and trigger an inflammatory response, as well as contribute to arteriosclerosis by inducing vascular damage. In the vasculature, endothelial cell death and dysfunction is accompanied by osteoblastic transformation and calcification of smooth muscle cells.

As calcium phosphate nanocrystals can cause renal epithelial injury by inducing oxidative stress, the CKD associated with high FGF23 levels might be, at least in part, due to damage caused by calcium phosphate or CPPs that are generated in the proximal tubular fluid. The fact that serum CPP levels are correlated with vascular calcification/stiffness and mortality in CKD patients suggests that CPPs may serve as a ‘pathogen’ of cardiovascular complications (Figure 2) [6].

Figure 2 : CPP-mediated inflammation and vascular damage [3]

References

1. Kuro-o M, Matsumura Y, Aizawa H, et al.. Mutation of the mouse klotho gene leads to a syndrome resembling ageing.. Nature. 1997; 390:45–51 . DOI: https://doi.org/10.1038/36285

2. Kuro-o M. . Klotho in health and disease. . Curr Opin Nephrol Hypertens. 2012;21(4):362-8. DOI: https://doi.org/10.1097/MNH.0b013e32835422ad

3. Kuro-o M. . The Klotho proteins in health and disease. . Nat Rev Nephrol. 2019;15(1):27-44. DOI: https://doi.org/10.1038/s41581-018-0078-3

4. Zhang Y, Xie Y, Berglund ED, et al. . The starvation hormone, fibroblast growth factor-21, extends lifespan in mice.. Elife. 2012;1:e00065. DOI: https://dx.doi.org/10.7554%2FeLife.00065

5. Li M, Qureshi AR, Ellis E, Axelsson J. . Impaired postprandial fibroblast growth factor (FGF)-19 response in patients with stage 5 chronic kidney diseases is ameliorated following antioxidative therapy. . Nephrol Dial Transplant. 2013;28 Suppl 4:iv212-9. . DOI: https://doi.org/10.1093/ndt/gft337

6. Kuro-o M. . Klotho and endocrine fibroblast growth factors: markers of chronic kidney disease progression and cardiovascular complications? . Nephrol Dial Transplant. 2019;34(1):15-21. . DOI: https://doi.org/10.1093/ndt/gfy126

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