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see original article on page 975

with CKD had significantly increased

FGF23 or PTH: which comes FGF23 and PTH levels and reduced calci-
triol and (modestly) calcium levels, all of
first in CKD? which characterize human CKD.
A closer look at the first few weeks after
Tamara Isakova1 and Myles S. Wolf1 CKD was induced revealed the first set of
novel findings reported in this study. A
In the past 40 years, disordered mineral metabolism has been among significant increase in FGF23 levels was
the most intensely studied areas of nephrology. A June 2010 PubMed already detectable in the CKD rats as com-
search for ‘secondary hyperparathyroidism and kidney disease’ yielded pared with the normal rats 10 days after
5866 references. Among these are papers documenting the development the antiglomerular basement antibodies
and application of numerous therapeutic agents—including calcitriol, were administered, which was when
follow-up blood was first sampled. Impor-
vitamin D analogs, phosphate binders, and cinacalcet—that remain in tantly, creatinine had increased only
widespread use in the day-to-day management of dialysis patients subtly at that point, and serum phosphate
worldwide. However, almost 6000 papers later, fundamental was unchanged. Only later, on day 20, did
pathophysiological concepts remain unclear, particularly regarding the the reduction in calcitriol levels and the
early pathogenesis of disordered mineral metabolism. increase in PTH achieve statistical sig-
Kidney International (2010) 78, 947–949. doi:10.1038/ki.2010.281
nificance. Serum phosphate levels finally
rose on day 30 after more severe renal
dysfunction developed. Consistent with
the known effects of FGF23 on vitamin D
Numerous factors contribute to maintain- 23 (FGF23), the recently discovered metabolism, and contrary to those of
ing elevated parathyroid hormone (PTH) phosphate—and vitamin D—regulating PTH, the animals with CKD demon-
levels in patients with advanced renal fail- hormone? This nephrology version of the strated a 50% reduction in 1--hydroxy-
ure. Through a variety of cellular mecha- chicken-or-the-egg conundrum is the lase expression and a fivefold increase in
nisms, hypocalcemia, hyperphosphatemia, subject of the report by Hasegawa et al.1 24-hydroxylase expression as compared
nutritional vitamin D deficiency, and in this issue of Kidney International. with the control animals. Collectively,
calcitriol deficiency increase either The investigators induced chronic these results provide direct experimental
parathyroid gland mass, secretion of PTH, glomerulonephritis in rats by injecting evidence in favor of the conceptual frame-
or both (Figure 1a). Although the litera- antiglomerular basement membrane anti- work of the primacy of increased FGF23
ture abounds with elegant diagrams that bodies in order to study the sequence of in the pathogenesis of secondary hyper-
demonstrate the complex interactions pathophysiological events underlying parathyroidism that was proposed by
between the main pathophysiological fac- disordered mineral metabolism in early clinical investigators studying patients
tors in disordered mineral metabolism in and progressive CKD. In a further step, with early CKD2,3 and supported by stud-
chronic kidney disease (CKD), a most they report the first application of neutral- ies of mice engineered to overexpress
basic, almost naive question has gone izing anti-FGF23 antibodies in an in vivo FGF23 (ref. 4) (Figure 1b).
largely unanswered: where does it all CKD model. They used the antibodies as This construct was confirmed by the
begin? Is an increased PTH level in a physiological probe to further dissect second set of novel results, which
response to hypocalcemia or phosphate the relative contributions of PTH and described the effects of treatment with
retention or calcitriol deficiency the key FGF23 in early CKD. anti-FGF23 antibodies. Within 24 h of
initiating factor in disordered mineral Over the first 4 weeks after the develop- administering the neutralizing antibodies,
metabolism in CKD, or is the primary ment of nephritis, serum creatinine nearly urinary fractional excretion of phosphate
driving force increased circulating doubled, but there was no difference in decreased and serum phosphate levels
concentrations of fibroblast growth factor serum phosphate levels as compared with rose to an extent commensurate with the
the control animals. The nephritic animals dose of antibody. Eliminating the effect of
1Division of Nephrology and Hypertension, maintained normal serum phosphate con- FGF23 with neutralizing antibody mark-
Department of Medicine, University of Miami centrations, despite consuming standard edly increased expression of 1--hydro-
Miller School of Medicine, Miami, Florida, USA 1% phosphorus chow, by increasing their xylase and decreased expression of
Correspondence: Myles S. Wolf, Division of urinary fractional excretion of phosphate 24-hydroxylase within 8 h of injection. As
Nephrology and Hypertension, Department of
by 65%. Indeed, the only nonsignificant a result, calcitriol levels increased signifi-
Medicine, University of Miami, Miller School of
Medicine, 1120 NW 14th Street, CRB 819, Miami, biochemical difference between the CKD cantly and in fact were completely
Florida 33136, USA. and control rats after 4 weeks was their normalized relative to the control animals.
E-mail: mwolf2@med.miami.edu serum phosphate level. By then, the rats This critical finding definitively confirms

Kidney International (2010) 78 947

co m m e nta r y
a b
PTH PTH
CaR VDR CaR VDR
FGFR Klotho
Serum Ca2+ 1,25D Normal
serum PO4
25D
FGF23
Serum PO4 1,25D
? Usual PO4
intake
Kidney disease
Kidney disease
Figure 1 | Pathogenesis of disordered mineral metabolism in CKD. (a) Traditional view of the
mechanisms that maintain secondary hyperparathyroidism in advanced chronic kidney disease.
(b) Updated view of the mechanisms that initiate secondary hyperparathyroidism in chronic
kidney disease, emphasizing the central role of FGF23. CaR, calcium sensing receptor; FGFR,
fibroblast growth factor receptor; PTH, parathyroid hormone; VDR, vitamin D receptor.
that increased FGF23 is the mechanism of FGF23 on day 10 is not clear. Additional
reduced calcitriol levels in early CKD and blood and urine samplings between days
discredits the view that insufficient renal 0 and 10 might have been instructive.
mass is an important early contributor. The findings of Hasegawa et al.1 help
Furthermore, the concept that abolishing extend our understanding of the patho-
FGF23 action can normalize calcitriol lev- genesis of disordered mineral metabolism
els suggests that clinical strategies that one step upstream from calcitriol defi-
reduce FGF23 might be a significant step ciency to FGF23 excess but they also beget
forward from our current reactive clinical the next logical question: what stimulates
management, which emphasizes treat- the early elevation of FGF23 in CKD? It is
ment with vitamin D after PTH is already unlikely that phosphate ‘retention’ could
elevated, toward a proactive strategy explain increased FGF23 as early as 10
of primary prevention of secondary days after the kidney was injured when, if
hyperparathyroidism itself. anything, there was a modest decrease in
In addition to the study’s strengths, its serum phosphate levels in the CKD rats.
limitations should also be noted. While Although this is unproven, we can specu-
Hasegawa et al.1 establish the sequence of late that injury or disease of the kidney
pathophysiological events in animals with itself might raise FGF23 levels directly,
progressive glomerulonephritis, it is likely even without a reduction in glomerular
that there are multiple avenues to second- filtration rate. Studies of patients with
ary hyperparathyroidism in humans. known kidney disease but preserved
These could differ by etiology of kidney glomerular filtration rate, such as certain
disease, and separate factors such as nutri- forms of nephrotic syndrome or early
tional vitamin D deficiency could drive stages of adult polycystic kidney disease,
increased PTH secretion independent of could be performed to test this hypothesis.
and before the rise in FGF23. Moreover, A primary reduction of klotho expression
although the model closely resembles the has been proposed as a mechanism of
biochemical phenotype in patients with FGF23 resistance that could stimulate
early CKD, the mechanism of the subtle increased FGF23 secretion.5 However, this
but significant decrease in serum calcium is unproven, and the reverse is equally
levels that coincided with the increase in plausible. Chronically elevated FGF23
948
levels in CKD could be the primary factor
that decreases klotho expression, as was
demonstrated in FGF23 transgenic mice.6
Finally, there could be other upstream
factors, such as changes in bone metabo-
lism, that might stimulate early increases
in FGF23 secretion. Investigators should
continue to focus on unraveling the
regulation of FGF23 secretion in CKD.
In the meantime, the report by Hasegawa
et al.1 has diagnostic and therapeutic
implications. These results indicate that
increased FGF23 is probably the most
sensitive biomarker of disordered phos-
phorus metabolism in early CKD and
certainly more sensitive than hyperphos-
phatemia. If interventions that lower
FGF23 are shown to improve patient
outcomes, screening FGF23 levels in CKD
patients could soon be integrated into
clinical practice. From a therapeutic
perspective, targeting dietary phosphorus
absorption has been the primary focus of
FGF23-lowering strategies.7 The current
study suggests a novel paradigm of directly
blocking the effects of FGF23 using mono-
clonal antibodies. This strategy might be
justified if FGF23 excess is found to be a
direct mediator of renal and cardiovascu-
lar toxicity related to disordered phospho-
rus metabolism rather than just a sensitive
biomarker of it. If so, blocking FGF23
could be particularly attractive for dialysis
patients, in whom FGF23 excess is
strongly associated with mortality,8 but it
plays a smaller role in regulating serum
phosphate because of lack of renal func-
tion. Although the risk of inducing severe
hyperphosphatemia would likely preclude
the use of anti-FGF23 antibodies in pre-
dialysis patients who rely on FGF23 to
augment urinary phosphate excretion, a
subtle component of the data presented by
Hasegawa et al.,1 on which the authors did
not comment, suggests a potential thera-
peutic opportunity even in predialysis
patients. Although the lower dose (0.1 mg/kg)
of anti-FGF23 antibody resulted in com-
plete restoration of calcitriol levels,
comparable to the effect of the higher dose
(1.0 mg/kg), the lower dose raised serum
phosphate only modestly compared with
the sharp increase caused by the higher
dose. Whether the differential effects on
phosphate handling versus calcitriol
production could be further dissociated
Kidney International (2010) 78
 co m m e nta r y

to minimize the risk of hyperphos- renal insufficiency. Am J Kidney Dis 2004; 44: -intercalated cell has its vacuolar H + -
phatemia is interesting but would require 250–256. ATPase inserted into the apical membrane
3. Gutierrez O, Isakova T, Rhee E et al. Fibroblast
extensive study. Establishing whether anti- growth factor-23 mitigates hyperphosphatemia and an anion exchanger, AE1, inserted into
FGF23 antibodies have a clinical role in but accentuates calcitriol deficiency in chronic the basolateral membrane. In contrast, in
CKD is one of many next logical steps in kidney disease. J Am Soc Nephrol 2005; 16: -intercalated cells, the H + -ATPase is
2205–2215.
the ongoing, comprehensive development 4. Bai X, Miao D, Li J et al. Transgenic mice inserted into the basolateral domain, and
plan of FGF23 for clinical practice. overexpressing human fibroblast growth factor 23 pendrin is the anion exchanger inserted
(R176Q) delineate a putative role for parathyroid into the apical membrane of these cells.
hormone in renal phosphate wasting disorders.
DISCLOSURE Regulation of net acid/base transport by
Endocrinology 2004; 145: 5269–5279.
MSW has served as a consultant or received
honoraria from Abbott Laboratories, Amgen,
5. Kuro-o M. Klotho in chronic kidney disease— collecting duct intercalated cells, induced
what’s new? Nephrol Dial Transplant 2009; 24: by systemic acid/base changes, is moder-
Davita, Genzyme, Lutipold, Novartis, Mitsubishi, 1705–1708.
and Shire. TI has received honoraria from Shire. 6. Marsell R, Krajisnik T, Goransson H et al. Gene ated by both short-term (minutes) and
expression analysis of kidneys from transgenic long-term (hours to days) processes.1
REFERENCES mice expressing fibroblast growth factor-23. It has been widely accepted that short-
1. Hasegawa H, Nagano N, Urakawa I et al. Direct Nephrol Dial Transplant 2008; 23: 827–833.
evidence for a causative role of FGF23 in the 7. Oliveira RB, Cancela AL, Graciolli FG et al. Early term acid/base regulation is achieved pri-
abnormal renal phosphate handling and vitamin control of PTH and FGF23 in normophosphatemic marily by exocytic insertion of sub-plasma
D metabolism in rats with early-stage chronic CKD patients: a new target in CKD-MBD therapy? membrane H + -ATPase-coated vesicles
kidney disease. Kidney Int 2010; 78: 975–980. Clin J Am Soc Nephrol 2010; 5: 286–291.
2. Shigematsu T, Kazama JJ, Yamashita T et al. 8. Gutierrez OM, Mannstadt M, Isakova T et al. into the plasma membrane and down-
Possible involvement of circulating fibroblast Fibroblast growth factor 23 and mortality among regulation by endocytic retrieval of the
growth factor 23 in the development of patients undergoing hemodialysis. N Engl J Med H + -ATPase back into the sub-membrane
secondary hyperparathyroidism associated with 2008; 359: 584–592.
vesicular pool in both - and -interca-
lated cells (Figure 1).1 The signal cascade
and molecular mechanism for acidosis-
see original article on page 993 induced exocytic insertion of the H + -
ATPase into the apical membrane of
Adaptation of intercalated cells -intercalated cells has been characterized
in some detail.2 Fusion of these vesicles is
along the collecting duct to SNARE dependent. Apical membrane syn-
taxin-1 and SNAP23 form complexes with
systemic acid/base changes VAMP-2 that is localized on the surface of
H + -ATPase-coated vesicles. This SNARE
John H. Schwartz1 and Edward A. Alexander1 fusion complex, along with N-ethylmale-
imide-sensitive factor (NSF), induces the
Collecting duct intercalated cells respond to short-term acid/base fusion of the vesicle with the apical mem-
brane. The signal cascade that activates
perturbations by rapidly shuttling H + -ATPase to and from the plasma
exocytosis in -intercalated cells is initiated
membrane. Purkerson et al. provide information on the regulation of the by a fall in cell pH and rise in cell calcium.3
anion transporters during chronic acidosis and acute recovery Recent evidence also points to a role for
(alkalosis). They found that the major mechanism for both acute and HCO3− -sensitive, soluble adenylate cyclase
chronic states is regulation of both the H + -ATPase and the anion in the signal cascade.4 The information for
exchangers plus changes in the overall expression level of these anion targeting of the H + -ATPase-coated vesicle
to the appropriate membrane (apical and/
transporters in chronic adaptation.
or basolateral domains) is in part contained
Kidney International (2010) 78, 949–951. doi:10.1038/ki.2010.343
within the H + -ATPase itself.5
Less attention has been paid to regula-
tion by changes in the systemic acid/base
Specialized cells along the collecting -intercalated cells are functional mirror status of the passive HCO3− exit step across
duct—- and -intercalated cells—carry images of one another. The -intercalated the basolateral membrane of -interca-
out acid or base secretion. The - and cell mediates H + secretion and the lated cells or the apical membrane of -
-intercalated cell HCO3− secretion. Acid/ intercalated cells. Although systemic
1Renal Section, Boston University Medical Center base secretion in these cells is driven by an acidosis induces increased basolateral
and Boston University School of Medicine, Boston, active pump, the vacuolar H + -ATPase, expression of AE1 in -intercalated cells
Massachusetts, USA
inserted into one plasma membrane and alkalosis increases expression of api-
Correspondence: John H. Schwartz, Evans
Biomedical Research Center, 650 Albany Street, domain, and there is a passive, base cal membrane pendrin in -intercalated
Boston, Massachusetts 02118-2908, USA. exit step, a Cl − / HCO3− exchanger, in cells, the mechanism for and kinetics of
E-mail: jhsch@bu.edu the opposite membrane domain. The these changes have not been elucidated.6,7

Kidney International (2010) 78 949