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Phosphorus and Survival: Key
Questions That Need Answers
REFERENCES Jorge B. Cannata-Andı́a and Manuel Naves-Dı́az
Bone and Mineral Research Unit, Hospital Universitario Central de
Asturias, Instituto Reina Sofı́a de Investigación, REDinREN del ISCIII,
1. Vande Walle JG, Donckerwolcke RA, van Isselt JW, Derkx FH, Joles
Universidad de Oviedo, Oviedo, Asturias, Spain
JA, Koomans HA: Volume regulation in children with early relapse of
minimal-change nephrosis with or without hypovolaemic symptoms. J Am Soc Nephrol 20: 234–236, 2009.
Lancet 346: 148 –152, 1995 doi: 10.1681/ASN.2008121277
2. Humphreys MH: Mechanisms and management of nephrotic edema.
Kidney Int 45: 266 –281, 1994
3. Hughey RP, Carattino MD, Kleyman TR: Role of proteolysis in the For more than forty years now, high serum phosphate levels, a
activation of epithelial Na⫹ channels. Curr Opin Nephrol Hypertens highly prevalent condition in patients with chronic kidney dis-
16: 444 – 450, 2007
4. Carattino MD, Sheng S, Bruns JB, Pilewski JM, Hughey RP, Kleyman
ease (CKD), have been associated with the pathogenesis of sec-
TR: The epithelial Na⫹ channel is inhibited by a peptide derived from ondary hyperparathyroidism, a common mineral and bone
proteolytic processing of its alpha subunit. J Biol Chem 281: 18901– disorder (MBD).1 Recent epidemiologic and experimental
18907, 2006 studies have further amplified the role this condition plays in
5. Bruns JB, Carattino MD, Sheng S, Maarouf AB, Weisz OA, Pilewski JM, the larger story of CKD-MBD. Experimental studies have demon-
Hughey RP, Kleyman TR: Epithelial Na⫹ channels are fully activated by
furin- and prostasin-dependent release of an inhibitory peptide from
strated that high phosphorus plays a key role in the development
the gamma-subunit. J Biol Chem 282: 6153– 6160, 2007 of vascular calcification2 and impairment of bone mass and
6. Diakov A, Bera K, Mokrushina M, Krueger B, Korbmacher C: Cleavage strength, induces changes in the expression pattern of muscle and
in the gamma-subunit of the epithelial sodium channel (ENaC) plays bone-related genes,3,4 and may also act as a pro-aging factor.5 In
an important role in the proteolytic activation of near-silent channels. addition, clinical studies have demonstrated an association
J Physiol 586: 4587– 4608, 2008
7. Carattino MD, Hughey RP, Kleyman TR: Proteolytic processing of the
among hyperphosphatemia, vascular stiffness, and left ventricular
epithelial sodium channel gamma subunit has a dominant role in hypertrophy.6 Taking all of the aforementioned findings together,
channel activation. J Biol Chem 283: 25290 –25295, 2008 it is reasonable to hypothesize all these untoward actions of phos-
8. Svenningsen P, Bistrup C, Friis UG, Bertog M, Haerteis S, Krueger B, phorus may ultimately affect mortality, as it has been suggested by
Stubbe J, Jensen ON, Thiesson HC, Uhrenholt TR, Jespersen B, several studies carried out in different dialysis cohorts.7,8
Jensen BL, Korbmacher C, Skøtt O: Plasmin in nephrotic urine acti-
vates the epithelial sodium channel. J Am Soc Nephrol 20: 299 –310,
The increase in the importance of phosphorus in the spec-
2009 trum of CKD-MBD also coincides with the description of the
9. Passero CJ, Mueller GM, Rondon-Berrios H, Tofovic SP, Hughey RP, multiple actions of a new modulator, fibroblast growth factor
Kleyman TR: Plasmin activates epithelial Na⫹ channels by cleaving the 23 (FGF-23). This phosphatonin carries out some effects inde-
gamma subunit. J Biol Chem 283: 36586 –36591, 2008 pendent of phosphorus, such as its inhibitory effect on parathy-
10. Vaziri ND, Gonzales EC, Shayestehfar B, Barton CH: Plasma levels and
urinary excretion of fibrinolytic and protease inhibitory proteins in
roid hormone synthesis,9 but, so far, most of the biologic actions
nephrotic syndrome. J Lab Clin Med 124: 118 –124, 1994 of FGF-23, including its recently described association with mor-
11. Wagner SN, Atkinson MJ, Wagner C, Hofler H, Schmitt M, Wilhelm O: tality,10 seem to be highly interdependent and related to phospho-
Sites of urokinase-type plasminogen activator expression and distri- rus, parathyroid hormone, and vitamin D metabolism.11,12
bution of its receptor in the normal human kidney. Histochem Cell Biol In this issue of JASN, Isakova et al.13 investigate in a pro-
105: 53– 60, 1996
12. Piedagnel R, Tiger Y, Lelongt B, Ronco PM: Urokinase (u-PA) is pro-
spective cohort of incident hemodialysis patients the hypoth-
duced by collecting duct principal cells and is post-transcriptionally esis that therapy with any type of phosphate binder versus no
regulated by SV40 large-T, arginine vasopressin, and epidermal phosphate binder offers survival benefit. To mimic a random-
growth factor. J Cell Physiol 206: 394 – 401, 2006 ized trial, they used an interesting approach, performing mul-
13. Adebamiro A, Cheng Y, Rao US, Danahay H, Bridges RJ: A segment of tivariate-adjusted “intention to treat” analysis and multivari-
gamma ENaC mediates elastase activation of Na⫹ transport. J Gen
Physiol 130: 611– 629, 2007
ate-adjusted “as treated” analysis in which the analyses started
14. Myerburg MM, Butterworth MB, McKenna EE, Peters KW, Frizzell RA, at the time the therapy began.
Kleyman TR, Pilewski JM: Airway surface liquid volume regulates In the intention-to-treat analysis, the phosphate binders
ENaC by altering the serine protease-protease inhibitor balance: A group offered a 30% lower mortality compared with the
mechanism for sodium hyperabsorption in cystic fibrosis. J Biol Chem untreated group. The results were less beneficial (18% lower
281: 27942–27949, 2006
15. Tarran R, Trout L, Donaldson SH, Boucher RC: Soluble mediators, not
cilia, determine airway surface liquid volume in normal and cystic fibrosis Published online ahead of print. Publication date available at www.jasn.org.
superficial airway epithelia. J Gen Physiol 127: 591– 604, 2006 Correspondence: Dr. Jorge B. Cannata-Andı́a, Bone and Mineral Research
Unit, Instituto Reina Sofı́a de Investigación, Hospital Universitario Central de
Asturias, C/ Julián Claverı́a s/n, 33006 Oviedo, Asturias. Phone:
⫹34985106137; Fax: ⫹34985106142; E-mail: metoseo@hca.es
See related article, “Plasmin in Nephrotic Urine Activates the Epithelial Sodium
Channel,” on pages 299 –310. Copyright 䊚 2009 by the American Society of Nephrology
234 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 231–238, 2009
