Article

The Relation between Renal Function and Serum

Sclerostin in Adult Patients with CKD
Solenne Pelletier,* Laurence Dubourg, Marie-Christine Carlier, Aoumeur Hadj-Aissa, and Denis Fouque*

Summary
Background and objectives Sclerostin, a bone antianabolic peptide involved in osteoporosis, is elevated in
patients undergoing maintenance dialysis. However, there are no data for patients with early CKD.
Design, setting, participants, & measurements Between January and July 2010, serum sclerostin and GFR (calculated
by inulin clearance) were measured in 90 patients with CKD. Fasting blood samples were also drawn for
determination of calcium, phosphorus, parathyroid hormone, bone alkaline phosphatase, and 25-OH vitamin D.
Results Median GFR was 66.5 (interquartile range, 40.088.3) ml/min per 1.73 m2. Median sclerostin level was
53.5 (interquartile range, 37.577.2) pmol/L, was higher in patients with a GFR ,60 ml/min per 1.73 m2, and was
highest in those with ESRD. Sclerostin levels were signicantly more elevated in men than women (P,0.05). An
inverse relationship was found between sclerostin and GFR (r=20.58; P,0.001), and a positive correlation was
seen with age (r=0.34; P,0.01) and serum phosphate (r=0.26; P=0.02). In multiple regression analyses, GFR, sex,
and serum phosphate were the only variables associated with serum sclerostin (P,0.001). Age lost its relationship with sclerostin level.
Conclusions This is the rst study reporting higher serum sclerostin levels starting at CKD stage III. GFR, sex, and
serum phosphate were the only measures associated with sclerostin level, suggesting that the effect of age
reported in the literature might instead be attributable to the altered renal function in the elderly. Correcting the
serum phosphorus level may be associated with lower sclerostin levels.
Clin J Am Soc Nephrol 8: 819823, 2013. doi: 10.2215/CJN.07670712

Introduction

Materials and Methods

Sclerostin is a recently identied osteocyte-derived

bone morphogenetic protein antagonist (1). Sclerostin
is the product of the SOST gene, which was discovered in 2001 (2). Inactivating mutations of the SOST
gene have been associated with sclerosteosis, a high
bone mass phenotype. Sclerostin is a Wnt signaling
pathway antagonist that results in negative regulation of bone formation by repressing differentiation
and proliferation of osteoblasts (3,4). It also promotes
osteoblast apoptosis. Increased sclerostin action is
thought to be involved in osteoporosis. In transgenic
mice overexpressing a normal human SOST gene, the
bone phenotype observed is an osteopenia; experimentally, blocking sclerostin action by a specic antibody induces more rapid tibial defect repair (5) and
an osteoanabolic effect (6). Sclerostin may affect bone
metabolism during CKD (7). In patients undergoing
maintenance dialysis, sclerostin has been reported to be
increased and associated with bone quality impairment
(8). To our knowledge, the reasons for this increase
have not been evaluated. We therefore designed a
cross-sectional study to assess, in patients with a
wide range of renal function who were not undergoing
dialysis, the relation of serum sclerostin with GFR and
its potential causes of accumulation.

Patients
The study involved 90 patients with a known
kidney disease who were referred for renal function
assessment in the Service dExploration Fonctionnelle
Rnale et Mtaboliques at Hpital Edouard Herriot
from January to July 2010. These outpatients were
attending a planned appointment and therefore did
not have acute disease that could have dramatically
modied their physical activity. Twenty volunteers
with no known kidney disease and a negative result
on urinary dipstick analysis (mean age 6 SD,
43.7611.1 years; estimated GFR, 93.5612.5 ml/min
per 1.73m2 [calculated according to the Modication
of Diet in Renal Disease formula]) served as controls.
The study protocol was described to all patients,
and each participant provided informed consent.

www.cjasn.org Vol 8 May, 2013

*Departement de
Nephrologie, Hopital
E. Herriot and
Universite de Lyon,
Lyon, France; Service
dExplorations
Fonctionnelles
Renales et
Metaboliques, Lyon,
France; and Hospices
Civils de Lyon, Service
de Biochimie,
Groupement
Hospitalier Sud, Pierre
Benite, France
Correspondence:
Dr. Solenne Pelletier,
Department of
Nephrology, Hopital
E. Herriot, 69437 Lyon
Cedex 03, France.
Email: Solenne.
pelletier@chu-lyon.fr

Kidney Function Measurement

GFR was measured by urinary inulin clearance
(ml/min per 1.73 m2) (9). Briey, inulin (Polyfructosan
[inutest], Laevosan, Linz, Austria) was infused continuously for 3 hours after a priming dose, and urine was
collected every 30 minutes by spontaneous voiding. Inulin was measured by the enzymatic method (10).
Copyright 2013 by the American Society of Nephrology

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Clinical Journal of the American Society of Nephrology

Blood Measurements
Blood was collected from all participants for determination
of various chemistries. Blood was drawn at 07:45 (before
breakfast and after an overnight fast). Samples were immediately chilled on ice and centrifuged at 3000 g; serum or
plasma was then separated, and samples were kept at 280
C until measurements. The following biologic data were recorded in patients with CKD: serum levels of calcium, phosphorus, bicarbonate, and intact parathyroid hormone
(measured with a second-generation assay: Elecsys, Roche
Diagnosis, Mannheim, Germany; normal values, 1565 pg/
ml) and 25-OH vitamin D (radioimmunologic assay: DiaSorin
Diagnosis, Saluggia, Italy; range of desirable values, 3080
ng/ml). Serum bone alkaline phosphatase was measured
with an Ostase assay (Beckman Coulter; normal values, 421
mg/L). Serum sclerostin was measured with a quantitative
sandwich ELISA (Biomedica Gruppe, Vienna, Austria). Intra-assay and interassay coefcients of variation were 4%
and 5.5%, respectively.
Statistical Analyses
Data were analyzed using SPSS software, version 18.0
(SPSS Inc., Chicago, IL). Data are presented as mean 6 SD or
as median (interquartile range [IQR]) when variables were
not normally distributed. Correlation between two variables
was assessed by simple regression. A multiple regression
model was used to dene the variables most predictive of
circulating sclerostin concentration after selection of the
measures found to be associated with sclerostin by simple
regression or known to be important in the physiology of
sclerostin: sex, body mass index, age, serum calcium, serum
phosphate, and GFR. A P value ,0.05 was considered to
represent a statistically signicant difference.

Results
Patients Characteristics
A cohort of 90 patients (46 women) with a median age of
52.0 years (IQR, 35.566.0 years) was recruited. The main
clinical and anthropometric characteristics of the study
population are summarized in Table 1.
Biochemical Measures
The median serum sclerostin level in patients was 53.5
(IQR, 37.577.2) pmol/L and was signicantly greater than
that in controls (38.2 [IQR, 27.157.8] pmol/L). Median
serum calcium level was 9.3 (IQR, 9.09.6) mg/dl, and
median phosphate level was 3.4 (IQR, 3.03.8) mg/dl.
Mean serum bicarbonate level was 25.263.2 mmol/L. Median serum bone alkaline phosphatase and median serum
parathyroid hormone levels were in the normal range: 11.9
(IQR, 9.116.2) mg/L and 54.5 (IQR, 36.797.3) pg/ml, respectively. Mean 25-OH vitamin D level was low
(20.668.7 ng/ml). Median proteinuria was mild at 0.22
(IQR, 0.110.43) g/d.
GFR
The median GFR was 66.5 (IQR, 40.088.3) ml/min
per 1.73 m2. Twenty patients had stage I CKD, 30 had
stage II, 25 had stage III, 12 had stage IV, and 3 had stage
V (Figure 1).

Table 1. Clinical and biochemical characteristics of patients

Characteristic

Value

Age (yr)
Men/women (n/n)
Body mass index (kg/m2)
Body weight (kg)
GFR (mL/min per 1.73 m2)
Serum calcium (mg/dl)
Serum phosphorus (mg/dl)
Serum parathyroid
hormone (pg/ml)
Serum 25-OH vitamin D
(ng/ml)
Serum sclerostin (pmol/L)
Serum bone alkaline
phosphatase (mg/L)
Serum bicarbonate (mmol/L)
Proteinuria (g/d)

52.0 (35.566.0)
44/46
25.3 (22.029.2)
71.0 (60.080.0)
66.5 (40.088.3)
9.3 (9.09.6)
3.4 (3.03.8)
54.5 (36.797.3)
20.668.7
53.5 (37.577.2)
11.9 (9.116.2)
25.263.2
0.22 (0.110.43)

Unless otherwise noted, data are presented as mean 6SD or as

median (interquartile range) when variables were not normally
distributed (n=90).

Relationships between Plasma Sclerostin and Clinical

and Biochemical Measures
The strongest relationship was observed between GFR
and serum sclerostin, and the correlation was negative
(r=20.58; P,0.001). Also important was age, which was
signicantly and positively correlated with serum sclerostin (r=0.34; P,0.01) (Figure 2). A positive relationship
was seen between serum phosphate and sclerostin
(r=0.26; P=0.02) (Figure 3). Body mass index was positively associated with serum sclerostin (r=0.22 P,0.05).
There was no further signicant relation between sclerostin and parathyroid hormone, serum calcium, serum bicarbonate, bone alkaline phosphatase, 25-OH vitamin D,
or proteinuria.
Regarding the expression of sclerostin by sex, we found
that sclerostin was more elevated in men than in women
(65.5 [IQR, 41.795.6] pmol/L versus 45.0 [IQR, 33.368.8]
pmol/L; P,0.05), as reported in healthy adults by Gennari
et al. (11) and Amrein et al. (12).
Serum sclerostin levels were also higher in male controls
than in female controls (40.5 [IQR, 36.266.2] pmol/L versus 35.7 [IQR, 26.049.8] pmol/L).
In men with CKD, we observed a signicant correlation
between sclerostin and age (r=0.56; P=0.001) and sclerostin
and body mass index (r=0.30; P=0.05). However, in contrast to Gennari and colleagues ndings, these relationships were less marked and were not signicant in
women, even though our study had twice the number of
observations as that study.
Multiple regression analysis that included sex, GFR, age,
body mass index, serum calcium, and phosphorus indicated that GFR (P=0.001), sex (P=0.01), and serum phosphate (P=0.02) were associated with serum sclerostin
(Table 2). Of note, in multiple regression analysis, age
was unrelated to sclerostin, possibly because of the major
effect that the decreased renal function seen with aging has
on sclerostin regulation. Sex, GFR, age, body mass index,

Clin J Am Soc Nephrol 8: 819823, May, 2013

Sclerostin in Patients with CKD, Pelletier et al.

821

Figure 1. | Serum sclerostin as a function of CKD stage based on GFR measured by inulin clearance. n=90; results are expressed as median
(interquartile range).

Figure 2. | Relationship between serum sclerostin and age. n=90; r=0.34; P=0.001.

Figure 3. | Relationship between serum sclerostin and serum phosphorus. n=90; r=0.26; P=0.016.

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Clinical Journal of the American Society of Nephrology

serum calcium, and serum phosphorus explained 38% of

the variance of serum sclerostin in this study (Table 2). In a
separate, three-factor model, GFR, sex, and serum phosphate explained 32% of the variance of serum sclerostin.

Discussion

To our knowledge, this is the rst study to show that

sclerostin, an antianabolic bone factor released by the
osteocyte, accumulates in patients with CKD who are not
undergoing dialysis. It is important to characterize this
abnormality because patients with CKD may be prone to
early adynamic bone disease, which may further induce
secondary hyperparathyroidism (13). Although sclerostin is
inuenced by age and other bone metabolic factors, such as
parathyroid hormone, 25-OH vitamin D, and sex steroids
(12,1417), we found by multiple regression that GFR, sex,
and serum phosphorus were the only measures associated
with sclerostin concentration in patients with CKD.

Patients with CKD Show High Sclerostin Levels Compared

with Healthy Volunteers
The median sclerostin level was 53.5 (IQR, 37.577.2)
pmol/L, was higher in patients with GFR ,60 ml/min
per 1.73 m2, and was highest in patients with ESRD. The
sclerostin values we report here at stage V before ESRD
(Figure 1) agree with those observed in patients undergoing maintenance hemodialysis. Indeed, Cejka et al. recently
showed in two different cohorts of such patients that sclerostin values were two to four times greater than those in
post- and premenopausal women without CKD (18) or
healthy volunteers (8). In this study, we found a fourfold higher serum sclerostin level in predialysis patients
with stage V CKD than in participants with normal renal
function. Thus, the abnormal sclerostin status observed
during maintenance dialysis (8,18) may just be the continuation of the predialysis stage alteration.
Main Measures Associated with Elevated Sclerostin Level
Renal function was one of the main measures associated
with elevated serum sclerostin levels in patients with CKD.

Table 2. Multivariate analysis of factors associated with serum

sclerostin (r2=0.38)

Variable

Age (yr)
Body mass index
(kg/m2)
Serum calcium
(mg/dl)
Serum phosphorus
(mg/dl)
Men
GFR (measured by
inulin; ml/min
per 1.73 m2)

Correlation
Coefcient for
Difference
in Sclerostin Level

P
Value

0.18
0.09

0.07
0.36

0.14

0.14

0.23

0.02

0.24
20.34

0.01
0.001

Of note, a study of diabetic patients reported a similar nding

in its control group (11); however, those investigators estimated renal function using the Cockcroft-Gault equation,
and the range of renal function should have been limited.
In a cohort of healthy adults, Amrein et al. (12) showed a
persistent effect of age after adjusting for GFR. However, renal function was in the normal range (84612 ml/min per 1.73
m2), patients were younger, and GFR was estimated (by the
MDRD formula) and thus was not a true GFR measurement.
Sclerostin is a small peptide of a 29-kD and 213amino acid
protein, and almost no data on its catabolism are available.
Sclerostin may be elevated in response to reduced renal clearance, as has been shown for many other peptides. However,
increased sclerostin production cannot be ruled out. Indeed,
in a genetic model of mice exhibiting progressive CKD, overall repression of Wnt/b-catenin pathway occurred in conjunction with increased expression of Wnt antagonists (e.g.,
sclerostin) along with increased osteoclast activity and repression of bone formation, particularly in ESRD (19). This model
of experimental CKD suggests that repression of the Wnt/
b-catenin pathway and its inhibitor sclerostin are involved in
the pathogenesis of renal osteodystrophy (19).
The fact that we found a positive relationship between
serum phosphate and sclerostin, independent of GFR, may
have clinical importance: Indeed, Matthew et al. (20), by
controlling serum phosphate through phosphate binders,
reversed CKD-induced trabecular osteopenia and thereby
increased osteoblast surfaces in the metaphyseal trabeculae of the tibia and femur, osteoid surfaces, and bone formation rates (20). There was no explanation for these
histomorphometric bone changes besides the reduction
in serum phosphorus, but this experiment did not measure
sclerostin. Because sclerostin varies proportionately with
serum phosphorus, it might have played a role in these
favorable changes. Documenting this observation in future
research may be of interest.

Age or Renal Function?

Another important nding of this study is the predominant effect of GFR and age on the regulation of serum
sclerostin observed in multiple regression analysis. Other
researchers have reported that serum sclerostin increases
with aging (21). In monovariate analysis, we also found
this relationship (Figure 2). However, because elderly patients have noticeably reduced renal function (not easily
deducible from serum creatinine), the positive association
between sclerostin and age could result from patients renal impairment, which is not precisely assessed in other
diseases. Thus, osteoporosis in the elderly may partly be
the consequence of elevated sclerostin values due to an
underestimated renal dysfunction.
It is important to note that this study was cross-sectional
and cannot determine causality. The clinical signicance of
the high sclerostin levels in CKD cannot be deduced from
the present results.
The sclerostin measurement techniques have been reviewed elsewhere (22). Two ELISA kits are available: One
from Biomedica, which we used in this study, and another
from TECOmedical (Sissach, Switzerland). In healthy
adults, these kits are not in perfect agreement; the former
gives values 50% greater than those of the latter. Possible

Clin J Am Soc Nephrol 8: 819823, May, 2013

binding of sclerostin fragments may occur, and this could

partly explain differences in recovery. No data are available on potential degradation fragments that could accumulate in CKD, as has been shown for PTH (23).
In conclusion, we showed a strong and inverse relationship between renal function and serum sclerostin levels in a
cohort of patients with CKD. In addition, serum phosphate
may be involved in the early and important elevation of
sclerostin. Because sclerostin is involved in low bone
turnover, it may be interesting to analyze the effects of
reducing sclerostin on bone mineral disorders long before
ESRD develops.

Sclerostin in Patients with CKD, Pelletier et al.

10.
11.

12.

13.
Acknowledgments
We are particularly indebted to the nurses of the Service dExploration Fonctionnelle Rnale et Mtabolique for excellent patients care.
This work was presented as an oral communication at the
American Society of Nephrology meeting in Philadelphia, Pennsylvania, in November 2011.

14.
15.

Disclosures
None.
16.
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Received: July 30, 2012 Accepted: January 8, 2013

Published online ahead of print. Publication date available at www.
cjasn.org.