Kidney Week 2014: The Wolf of Kidney Week
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.
This is a nice summary of what Michelle Winn contributed to Nephrology and to all of Duke http://t.co/RrwxyiPsc0 #kidneywk14 #mentor #leader
— Matthew Sparks, MD (@Nephro_Sparks) November 16, 2014
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.
Wolf: higher phosphate are independently associated with heart disease. In ESRD, in CKD and non-renal disease #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
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?
Wolf: PTH increases phosphate clearance. If you restrict phos their circulating 1,25D increase and PTH decrease #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
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.
Wolf: this was presumptive evidence for the existence of phosphotonin. #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
Study of rare diseases was pivotal in identification of FGF23 as key regulator of calcium and phosphate | Myles Wolf #kidneywk14
— Nature Reviews Nephrology (@NatRevNeph) November 16, 2014
@kidney_boy Causes of Primary and Secondary FGF23 Excess and Deficiency #KidneyWk14 http://t.co/6psO9IVPNR pic.twitter.com/lkXzT01KNH
— Edgar V. Lerma 🇵🇭 (@edgarvlermamd) November 16, 2014
FGF-23 is secreted by osteocytes and completed the bone/kidney/parathyroid triangle. It actually was more of a loopy thing as illustrated below:
@kidney_boy Physiologic actions of FGF23 #KidneyWk14 http://t.co/6psO9IVPNR pic.twitter.com/WxSqUxSw0F
— Edgar V. Lerma 🇵🇭 (@edgarvlermamd) November 16, 2014
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.
FGF23 increases early in rats with CKD, before changes in calcitriol, serum phosphate | Myles Wolf #kidneywk14
— Nature Reviews Nephrology (@NatRevNeph) November 16, 2014
Here is the cross sectional data from CRIC:
https://storify.com/kidney_boy/asn-kidneywk14-sunday-plenary-session
Animal study: Neutralizing fgf23 antibodies: phos goes up dramatically. So FGF23 is critical for phase regulation #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
@kidney_boy Temporal aspects of disordered Phosphorus metab in progressive CKD #KidneyWk14 http://t.co/6psO9IVPNR pic.twitter.com/ALuOO9MYFp
— Edgar V. Lerma 🇵🇭 (@edgarvlermamd) November 16, 2014
Looking at FGF-23 being elevated in CKD he wondered if it had prognostic significance in dialysis:
Higher the FGF23 the day you start dialysis the lower the likelihood you would survive a year on dialysis #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
This FGF finding was not confounded by anything. Unheard of in ESRD research. #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
This lead to the thought that FGF23 was more than just a marker and the actual culprit #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
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:
FGF23 and LVH. LVH is a potent risk factor for death. Higher FGF23 with increased LVH @CricStudy again! #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
In vitro studies also showed pathogenic potential of FGF-23
Wolf describing Faul’s nice study in JCI 2011: FGF23 induces hypertrophy of cultured cardiomyocytes, indicating direct effect #kidneywk14
— Nature Reviews Nephrology (@NatRevNeph) November 16, 2014
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.
They suspected isoform 4. AB to isoform 4 and knock out models without 4, were protected. #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
Knock in model with constitutively active isoform 4 get spontaneous LVH #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
Maybe in the future maybe we will be able to selectively block the isoform 4-cardiotoxic FGF-23 receptor. #kidneywk14
— Joel M. Topf, MD FACP (@kidney_boy) November 16, 2014
Nice overview of phosphate & FGF23 in CKD and CVD. For more details check out Wolf’s recent review #kidneywk14 http://t.co/org8LbW1pt
— Nature Reviews Nephrology (@NatRevNeph) November 16, 2014
Interesting food for thought. Great work from Dr. Wolf.
Post written by Dr. Joel Topf, eAJKD Advisory Board member.
Check out more of eAJKD’s coverage of Kidney Week 2014! Also, follow @eAJKD on Twitter for live updates!
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