Concept Maps: Bone disease, FGF-23 and more..

 

references

https://www.kidney-international.org/article/S0085-2538(15)54255-5/fulltext

https://jasn.asnjournals.org/content/18/3/875

Special post by 

Lakshmi Kannan, MBBS, MD, 

Department of Nephrology, Pikeville Medical Center

Adjunct Faculty, University of Pikeville Kentucky College of Osteopathic Medicine

Kentucky, USA

Journal Club: FGF-23 and LVH

Left ventricular hypertrophy(LVH) is an important mechanism of cardiovascular disease in CKD that contributes to cardiac events and death. Prevalence of LVH in dialysis population is around 90% and 50-70% in CKD population. Compensatory increases in FGF23 levels help patients with CKD to maintain normal serum phosphate levels, despite even severely reduced renal function. Recent prospective studies of CKD and non-CKD patients demonstrated a dose-dependent association between elevated FGF23 levels and greater risks of major cardiovascular events and mortality.

http://www.ncbi.nlm.nih.gov/pubmed/21903574
http://www.ncbi.nlm.nih.gov/pubmed/18687639
http://www.ncbi.nlm.nih.gov/pubmed/21673295 

A recent study by Faul et al in JCI show the toxicity of elevated FGF-23 levels on LVH in a mice model. They summarize that FGF23 causes pathological cardiac hypertrophy directly. This is mediated by FGFR-dependent activation of the calcineurin-NFAT signaling cascade but do not require klotho as coreceptor. Blocking FGFR signaling can prevent LVH, independent of blood pressure in an established animal model of CKD that is characterized by elevated FGF23 levels, severe hypertension, and LVH. The effect is Klotho independent. First, low-affinity binding of FGF23 to FGFR may be adequate to induce LVH when there is a protracted period of cardiac exposure to high concentrations of FGF23, such as in CKD. FGF23 toxicity : accentuated further in CKD where klotho expression is down-regulated in the kidney and parathyroid glands, which could enhance promiscuous binding of FGF23 to FGFR in other tissues.

Thus, high circulating FGF23 concentrations combined with decreased klotho expression could represent an especially cardio-toxic blend in patients with CKD.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21985788
(image courtesy:- JCI article)

Hitesh Patni, MD

Kenar Jhaveri, MD

FGF-23 and Mortality Journal Club

FGF-23 and Mortality in Dialysis patients- Journal Club

View more presentations from Nephrology, NSLIJ

CLINICAL CASE 40: ANSWERS AND SUMMARY

Besides phosphate metabolism, what other functions does the klotho gene have associations with?

insulin resistance	5 (11%)
thyroid disease	0 (0%)
aging	35 (81%)
development of the hypothalamus	0 (0%)
sensory neuron development	3 (6%)

Interesting history regarding Klotho. The gene actually was first identified as a aging suppressor gene that extended life span before it got its glory in FGF 23 and phosphate regulation. So Aging is the right answer.  Klotho is also an obligate co receptor to FGF 23( which suppresses phosphate reabsorption and 1,25 Vit D synthesis in the kidney).

Klotho actually means "who spun the thread of life".  The klotho knockout mouse has the following finding:

faster aging, hypogonadism, growth retardation, atrophy of skin, cognition impairment.

The transgenic Klotho mice have increase in lifespan. FGF 23 def mice are similar to Klotho def mice and hence the relation came about.  Some studies show that it is the phosphate retention that causes extensive aging like features. It is not surprising that it is the phosphate that really makes the big difference in CKD and dialysis patients.  

Interesting concepts

Check out ref:

http://www.ncbi.nlm.nih.gov/pubmed/19329831

http://www.ncbi.nlm.nih.gov/pubmed/21164022

http://www.ncbi.nlm.nih.gov/pubmed/21496980