Myles Wolf wins the Young Investigator Award on Sunday in the final plenary session of Kidney Week. The Sunday is a more sedate than the Thursday, Friday and Saturday. All of the vendors have gone home and most of the attendees have joined them. However the session has some of the best moments. They started off with the In Memorium video honoring the nephrologists that have died in the last year.
The last one they showed was Dr. Michelle Winn, who won the Young investigator award in 2007 and discovered TRPC6, a gene involved in the podocyte slit membrane.
Then they announced the winner of this year’s young investigator award: Myles Wolf. Dr. Wolf then gave a talk titled Mineral Maladaptation. He began his talk stating there are two sides to disease research you can look to the mechanisms that cause disease in the organ interest or you can look at the diseases that result from the dissuasion the organ of interest. He has focused his career on the latter.
This is an interesting observation but what is more interesting is that the phosphate is usually maintained in the normal level to profound degrees of GFR loss. In fact half of patients initiate dialysis with a normal phosphorus level.
The sodium phosphate transporter in the proximal tubule normally reabsorbs nearly all of the filtered phosphorus and be decreasing the activity of this transporter normal phosphorus balance can be maintained down to very low GFRs. What are the signals that direct this adaptation?
This observation was revolutionary to Wolf because since PTH stimulates 1,25 OHD the observation of falling PTH and rising 1,25 OHD indicates another substance must be in the mix controlling phosphorus metabolism.
FGF-23 is secreted by osteocytes and completed the bone/kidney/parathyroid triangle. It actually was more of a loopy thing as illustrated below:
Renal affects of FGF-23 are dependent on expression of the anti-aging protein Klotho. After the discovery FGF-23 things began to accelerate with the development of a reliable assay to measure it. This lead to widespread studies of FGF-23 in CKD. He is using the data from the CRIC study to prove that increases in FGF-23 is the earliest metabolic abnormality in bone metabolism in CKD. Longitudinal human studies are forthcoming but for now he is using animal data.
Here is the cross sectional data from CRIC:
Looking at FGF-23 being elevated in CKD he wondered if it had prognostic significance in dialysis:
Could FGF-23 be more than merely a marker of disease but actually be the pathogenic agent? Knocking out FGF-23 completely lead to lethal hyperphosphatemia so that wasn’t the answer. He did find that FGF-23 was correlated with LVH in CKD:
In vitro studies also showed pathogenic potential of FGF-23
Since kidney disease leads to both increased FGF-23 and vascular calcification, Wolf thought that the FGF-23 was the cause of the calcification, however the CRIC data showed no association between FGF-23 and vascular calcification. This lead him to believe that FGF-23 causes LVH and CHF, while hyperphosphatemia is the cause of vascular calcification. Sometimes, it’s not one explanation.
He discovered that the FGF-23 effect on the heart could not be neutralized by loss of Klotho, it looked like the cardiac FGF-23 receptors were cloth independent. There are 4 isoforms of the FGF-23 receptors and it turns out that the fourth isoform is Klotho independent and responsible for the cardiac toxicity.
Interesting food for thought. Great work from Dr. Wolf.
Post written by Dr. Joel Topf, eAJKD Advisory Board member.