Introduction: Sclerostin could enhance renal excretion of calcium (Ca) and phosphate (P). The association between sclerostin and magnesium (Mg) has not yet discovered. In patients with type 2 diabetes mellitus (T2DM) or chronic kidney disease (CKD), higher serum sclerostin and altered renal excretion of Ca, P, and Mg were detected. Therefore, we tried to evaluate if there was any association between sclerostin and fractional excretion of Ca, P, and Mg (FeCa, FeP, and FeMg) in T2DM with CKD. Methods: In this prospective cohort study, 43 T2DM patients without CKD or with CKD stage 1–5 were enrolled. Values of parameters, including serum and urine sclerostin, were collected at baseline and 6 months later. For baseline data, the Mann-Whitney U test, χ2 test, or Spearman’s correlation were used. For multivariate repeated measurement analysis, generalized estimating equation (GEE) model was utilized. Results: Patients with lower estimated glomerular filtration rate had higher serum sclerostin, FeP, FeMg, and lower FeCa. By correlation analysis, serum sclerostin was negatively associated with FeCa (p = 0.02) and positively associated with FeP (p = 0.002). The urine sclerostin to creatinine ratio (Uscl/Ucre) was positively correlated with FeP (p = 0.007) and FeMg (p = 0.005). After multivariate analyses by GEE model, serum sclerostin was still inversely associated with FeCa, while Uscl/Ucre was significantly associated with FeMg. On the other hand, FeP lost its associations with serum sclerostin or Uscl/Ucre. Conclusion: In our study population of T2DM patients with or without CKD, the inverse correlation between serum sclerostin and FeCa could not be explained by the calciuric effect of sclerostin. In addition, a newly discovered positive association between urinary sclerostin and FeMg indicated a possible role of urinary sclerostin in regulating renal Mg handling especially over distal convoluted tubules.

Sclerostin, encoded by SOST gene, is a secreted glycoprotein mainly produced by mature osteocytes. It is known to inhibit Wnt-β-catenin pathway, thus inhibiting osteoblast differentiation and subsequently bone formation [1]. Clinically, serum sclerostin level was higher in patients with type 2 diabetes mellitus (T2DM) or chronic kidney disease (CKD) [2]. In T2DM, higher serum sclerostin, possibly due to enhanced osteocyte production by hyperglycemia or inflammatory status [3-5], is recognized as a risk factor for osteoporosis [6]. While in CKD, higher serum sclerostin, possibly resulting from enhanced production instead of reduced renal clearance [7], has been shown to be associated with bone metabolism [7-10], arterial stiffness [11], vascular calcifications [12], cardiovascular events as well as mortality [13].

Various alterations of renal calcium (Ca) and phosphate (P) handling are observed in T2DM and CKD. Hypercalciuria has been found in uncontrolled T2DM, which could be explained by osmotic diuresis, glucose ingestion, and decreased renal alpha-Klotho expression [14-16]. In addition, increased renal P loss has also been detected in T2DM, which may be the consequence of negative bone balance [16]. On the other hand, the decline in urinary Ca excretion during CKD progress could be partly explained by low 1α,25-dihydroxy vitamin D [1α,25-(OH)2D] [17] and high parathyroid hormone (PTH) levels [18]. In the opposite, the negative correlation between urinary P excretion and the glomerular filtration rate (GFR) [17, 19] is probably due to elevated fibroblast growth factor 23 (FGF23) and PTH in response to P retention [20]. Moreover, sclerostin was found not only to inhibit the synthesis of 1α hydroxylase by cultured proximal tubular cells [21], but also to indirectly stimulate the secretion of FGF23 by osteoblasts [22]. Therefore, urinary Ca excretion was lower in sost−/− mice than in wild type mice [21]. In addition, serum sclerostin was shown to be correlated with urinary P excretion in CKD population [7].

Renal handling of magnesium (Mg) shares many similar regulatory mechanisms such as PTH, 1α,25-(OH)2D, Ca sensing receptor, and claudin [23] as that of Ca and P. In addition, enhanced renal Mg excretion was also found in CKD [24] and DM [25], but the underlying mechanisms were mainly based on assumptions. In CKD, it was believed to be the compensation for loss of renal function [24], while in DM, enhanced filtered load due to glomerular hyperfiltration or proteinuria or reduced renal reabsorption resulting from insulin deficiency or resistance might be the reason [25]. Since hypomagnesemia was linked to several chronic diabetic complications in T2DM patients [25], it is necessary to explore the underlying mechanism to further develop proper management against hypomagnesemia in this population.

Since sclerostin could promote renal Ca and P excretion at least by inhibiting production of 1α,25-(OH)2D [21], it was interesting to investigate if sclerostin was linked to altered renal handling of Ca and P in T2DM or CKD. Moreover, sclerostin has not yet been shown to have any relationship with renal Mg handling. Since higher serum sclerostin and enhanced renal Mg excretion both existed in T2DM and CKD, it was of interest to know if sclerostin had any association with renal Mg handling in these populations. Accordingly, a prospective cohort study was designed to evaluate possible associations between sclerostin and urinary excretion of Ca, P, and Mg in T2DM patients within different stages of CKD.

Study Population

From September to December 2015, around 2,400 patients visiting Nephrology Outpatient Department in E-Da Hospital, Kaohsiung, had been screened. T2DM patients with age ≥20 years, no new onset fracture, and no exposure to vitamin D and its analogues, diuretics, steroid, Ca-containing medications, or treatment for osteoporosis in recent 3 months were enrolled in this study. In opposite, patients with pregnancy, cancer, liver disease, renal replacement therapy including hemodialysis, peritoneal dialysis, and renal transplantation, or active infection were excluded. Finally, 43 patients were enrolled in this study. Written informed consent was obtained from these patients. The study was approved by the Institution Review Board of the hospital (number EMRP-104-045) and was in adherence with the Declaration of Helsinki.

Demographic and Lab Data Collection

For each patient, we recorded clinical parameters including age, sex, body mass index, the diagnosis of hypertension, and blood pressure. The medication for diabetes within 3 months before the acquisition of baseline data was also recorded. In addition, fasting blood and randomly spot urine samples were collected. Creatinine, albumin, Ca, P, Mg, glycated hemoglobin (HbA1c), sclerostin, bone-specific alkaline phosphatase (BAP), collagen type 1 cross-linked C-telopeptide (CTX), intact PTH (iPTH), FGF23, 25-OHD, and soluble alpha-Klotho (sKlotho) were measured in serum or plasma. Estimated GFR (eGFR) was calculated using modification of diet in renal disease equation. On the other hand, urine total protein, creatinine, Ca, P, Mg, and sclerostin were measured. Urine protein-creatinine ratio (UPCR), fractional excretion of Ca, P, and Mg (FeCa, FeP, and FeMg) were then calculated accordingly.

Assays

Serum creatinine, albumin, Ca, P, Mg, and 25-OHD as well as plasma HbA1c and iPTH were measured at Department of Laboratory Medicine in E-Da Hospital. Serum creatinine was measured by the Jaffe method with Clinimate CRE reagent on TOSHIBA-C16000 analyzer. With Abbott i2000 immunology analyzer, serum 25-OHD and plasma iPTH were assayed by chemiluminescent microparticle immunoassay using ARCHITECT 25-OH vitamin D reagent (Abbott, Germany) and ARCHITECT iPTH reagent (Abbott, Germany), respectively.

Serum and urine sclerostin were measured by enzyme-linked immunosorbent assay (ELISA) (BI-20492; Biomedica, Austria) with inter- and intra-assay variation ≤10 and ≤7%, respectively. The detection limit was 3.2 pmol/L. Serum BAP was measured by Ostase® BAP immunoenzymetric assay (AC-20F1, IDS, UK) with both inter- and intra-assay variation <7%. The detection limit was 0.7 µg/L. Serum CTX was measured by ELISA (SL0540Hu; SunLong Biotech, China) with inter- and intra-assay variation <12 and <10%, respectively. The detection limit was 12.5 pg/mL. Serum FGF23 was assayed with a commercially available kit (CY-4,000; Kainos Lab, Japan) with inter- and intra-assay coefficients of variation <5%. The lower limit of detection was 3 pg/mL. Serum sKlotho was assayed with ELISA (27,988; IBL, Japan) with within- and between-run variation <5 and <8%, respectively. The lower limit of detection was 6.15 pg/mL.

Statistical Analysis

The normality of all parameters was analyzed by the Shapiro-Wilk normality test. Many parameters including serum sclerostin (p = 0.019), BAP (p < 0.001), FGF23 (p = 0.014), sKlotho (p < 0.001), plasma HbA1c (p < 0.001), iPTH (p = 0.001), UPCR (p = 0.009), and FeCa (p < 0.001) were not normally distributed, and our sample size was relatively small. Therefore, nonparametric statistics were utilized in this study. Continuous variables were expressed as median (Q1, Q3) and categorical variables were expressed as frequency (percentage). To compare baseline parameters between low eGFR and high eGFR groups, the Mann-Whitney U test or χ2 test was adopted. In addition, Spearman’s correlation was chosen for correlation analysis of baseline data. Finally, generalized estimating equation (GEE) was used for multivariate repeated measurement analysis. In GEE model, the covariance structure was set as first order autoregressive. Corrected quasi-likelihood under independence model criterion was applied for choosing the best sets of parameters. Lower corrected quasi-likelihood under independence model criterion indicated better fit. All statistical analyses were performed in SPSS version 19. Two-sided p < 0.05 was considered as statistically significant.

Baseline Characteristics of Study Population

Finally, 43 patients had their baseline data and 33 of them had their second data 6 months later. Their baseline characteristics are shown in Table 1. The median age was 59 years and 31 patients (72.1%) were male. Thirty-four (79.1%) of them had hypertension. The median eGFR was 55.2 mL/min/1.73 m2 (13 without CKD, 4 in CKD stage 2, 21 in CKD stage 3, 2 in CKD with stage 4, and 3 in CKD stage 5), median UPCR was 321 (74.9, 1,207) mg/g, and median HbA1c was 6.9 (6.60, 8.20) %. The numbers of patients receiving different kinds of medication for T2DM were listed as below: 10 (23.3%) for insulin, 18 (41.9%) for metformin, 35 (81.4%) for dipeptidyl peptidase 4 inhibitors, 31 (72.1%) for sulfonylurea, 1 (2.3%) for repaglinide, 15 (34.9%) for acarbose, and 2 (4.7%) for pioglitazone.

Table 1.

Baseline parameters of study population

Baseline parameters of study population
Baseline parameters of study population

Comparison between Patients with Lower or Higher eGFR

These 43 patients were further divided into 2 groups according to their baseline eGFR: low eGFR (<60 mL/min/1.73 m2) or high eGFR (≥60 mL/min/1.73 m2). As shown in Table 1, patients with low eGFR were older in age (p = 0.005) and had higher serum sclerostin (p = 0.009), FGF23 (p = 0.003), UPCR (p = 0.001), FeP (p = 0.004), and FeMg (p < 0.001) but lower FeCa (p = 0.03) compared to those with higher eGFR. On the other hand, there was no significant difference in systolic, diastolic, and mean blood pressure, serum Ca, P, Mg, BAP, CTX, 25-OHD, and sKlotho, plasma iPTH and HbA1c, and urine sclerostin to creatinine ratio (Uscl/Ucre) between groups.

Factors Associated with Serum and Urine Sclerostin

By correlation analysis of baseline data (see online suppl. Table 1; see www.karger.com/doi/10.1159/000516844 for all online suppl. material), serum sclerostin was positively correlated with serum FGF23 (r = 0.507, p = 0.001), UPCR (r = 0.306, p = 0.046), and FeP (r = 0.469, p = 0.002), and negatively associated with eGFR (r = −0.517, p < 0.001) and FeCa (r = −0.355, p = 0.046). Multivariate analysis by GEE model showed that after adjustment by eGFR, FGF23, UPCR, and FeP, serum sclerostin was still negatively associated with FeCa (r = −5.350, p = 0.037). In online suppl. Table 2, baseline Uscl/Ucre was correlated positively with FeP (r = 0.413, p = 0.007) and FeMg (r = 0.424, p = 0.005), and negatively with serum albumin (r = −0.336, p = 0.03). After adjustment by serum albumin and FeP using GEE model, Uscl/Ucre was still associated positively with FeMg (r = 4.102, p = 0.005).

The Association between Sclerostin and FeCa, FeP, and FeMg

We further investigated the association between sclerostin and FeCa, FeP, or FeMg. As shown in Table 2, baseline serum sclerostin (r = −0.355, p = 0.020), not Uscl/Ucre, was inversely correlated with FeCa by correlation analysis. The scatterplot of serum sclerostin and FeCa was shown in Figure 1a. After correcting for eGFR, FGF23, sKlotho, and UPCR (model 1) or eGFR, sKlotho, iPTH, and 25OHD (model 2) by GEE, FeCa was still inversely associated with serum sclerostin (r = −0.008, p = 0.034 in model 1 and r = −0.009, p = 0.019 in model 2). Besides, it is noteworthy that although iPTH was not correlated with FeCa in correlation analysis, it became negatively associated with FeCa in GEE model 2 (r = −0.004, p = 0.046).

Table 2.

Univariate correlation with FeCa and multivariate analyses by GEEs

Univariate correlation with FeCa and multivariate analyses by GEEs
Univariate correlation with FeCa and multivariate analyses by GEEs
Fig. 1.

The scatterplot of baseline serum sclerostin and FeCa (a), and baseline urinary sclerostin (represented as Uscl/Ucre) and FeMg (b). By Spearman’s correlation, baseline serum sclerostin was inversely correlated with FeCa (r = −0.355, p = 0.020), while baseline Uscl/Ucre was correlated with FeMg (r = 0.424, p = 0.005). Uscl/Ucre, urine sclerostin to creatinine ratio; FeCa, fractional excretion of calcium; FeMg, fractional excretion of magnesium.

Fig. 1.

The scatterplot of baseline serum sclerostin and FeCa (a), and baseline urinary sclerostin (represented as Uscl/Ucre) and FeMg (b). By Spearman’s correlation, baseline serum sclerostin was inversely correlated with FeCa (r = −0.355, p = 0.020), while baseline Uscl/Ucre was correlated with FeMg (r = 0.424, p = 0.005). Uscl/Ucre, urine sclerostin to creatinine ratio; FeCa, fractional excretion of calcium; FeMg, fractional excretion of magnesium.

Close modal

In Table 3, baseline FeP was correlated with serum sclerostin (r = 0.469, p = 0.002) and Uscl/Ucre (r = 0.413, p = 0.007). After multivariate analysis by GEE model, both serum sclerostin and Uscl/Ucre lost their associations with FeP. Instead, FeP was significantly associated with eGFR (r = −0.273, p < 0.001 in model 1 and r = −0.237, p < 0.001 in model 2) and iPTH (r = 0.053, p = 0.032 in model 2).

Table 3.

Univariate correlation with FeP and multivariate analyses by GEEs

Univariate correlation with FeP and multivariate analyses by GEEs
Univariate correlation with FeP and multivariate analyses by GEEs

In Table 4, baseline FeMg was correlated with Uscl/Ucre (r = 0.424, p = 0.005), not serum sclerostin. The scatterplot of Uscl/Ucre and FeMg is shown in Figure 1b. After correcting for age, eGFR, serum albumin, FGF23, UPCR, FeP (model 1) or eGFR, FGF23, and iPTH (model 2) by GEE, FeMg was still associated with Uscl/Ucre (r = 0.015, p = 0.017 in model 1 or r = 0.023, p = 0.027 in model 2). In addition, there was no significant association between FeMg and iPTH.

Table 4.

Univariate correlation with FeMg and multivariate analyses by GEEs

Univariate correlation with FeMg and multivariate analyses by GEEs
Univariate correlation with FeMg and multivariate analyses by GEEs

In this study, we have successfully shown that in T2DM patients with or without CKD, sclerostin has impacts on renal excretion of Ca, P, and Mg in different aspects. Serum sclerostin had significant association with FeCa; Uscl/Ucre, as a marker for urine sclerostin, was strongly associated with FeMg. In our study population, serum sclerostin has been shown to negatively correlate with FeCa even after adjustment by eGFR, sKlotho, iPTH, and 25OHD. It indicates that sclerostin is not responsible for hypercalciuria seen in T2DM. Indeed, hypercalciuric effect in T2DM could be due to the osmotic effect [26] or decreased renal alpha-Klotho expression [15]. In addition, sclerostin was considered to increase renal Ca excretion by downregulation of vitamin D activity [27]. Therefore, the inverse relationship between serum sclerostin and FeCa in our T2DM patients with or without CKD may reflect a possible new negative feedback of FeCa on sclerostin, which has not yet been described before. Further studies are needed to confirm this hypothesis.

Compared with serum sclerostin, urinary sclerostin was seldom investigated before. In CKD population, urinary sclerostin, Uscl/Ucre, and fractional excretion of sclerostin, remained relatively low in CKD stage 1–3 but dramatically increased with wider variability when eGFR <30 mL/min/1.73 m2 [7]. Based on the detection of sclerostin in human proximal tubular cells [7] and its relatively low molecular mass (∼28 kDa), sclerostin was estimated to be filtered through glomerular basement membrane and appear in urine if its filtered amount exceeds the reabsorptive capacity of tubular cells [7]. On the other hand, renal sclerostin expression was also demonstrated in the human kidney tissue [27], but the exact location for renal sclerostin expression was not identified. Therefore, the appearance of sclerostin in urine may be due to its filtered amount exceeding renal tubular reabsorptive capacity or increased renal production. In this study, Uscl/Ucre was not correlated with eGFR, which may be due to an uneven distribution of CKD stages in our patients (only 5 in CKD stage 4–5).

It is a novel finding to show the significant association of Uscl/Ucre and FeMg in our study population. In the kidney, about 96% of filtered Mg is reabsorbed by tubules (40–70% in thick ascending limb [TAL] and 5–10% in distal convoluted tubule [DCT]). While Mg reabsorption in TAL shares the same paracellular pathway with Ca reabsorption, Mg reabsorption in DCT, acting through active transcellular pathway, fine-tunes the final renal Mg excretion. On the apical membrane of DCT, the voltage-gated potassium channel Kv1.1 creates polarization of apical membrane, driving Mg to enter the cell via the Mg channel, melastatin-related transient receptor potential cation channel 6 (TRPM6). The epidermal growth factor can bind to the epidermal growth factor receptor on the basolateral membrane of DCT and finally increases the activation and surface expression of TRPM6 [23, 28]. In addition, inhibition of apical sodium-chloride cotransporter by thiazides was also shown to enhance Mg excretion by downregulation of TRPM6 [29]. Moreover, PTH, calcitonin, glucagon, and even vasopressin were all implicated to regulate Mg reabsorption at DCT at least partly by stimulation of cyclic adenosine monophosphate release and activation of protein kinase A as well as activation of phospholipase C and then protein kinase C [30]. Importantly, no data have linked sclerostin to renal Mg handling yet. In this study, Uscl/Ucre was found to be significantly associated with FeMg, but not FeCa. Therefore, we hypothesize that sclerostin in urine may regulate Mg reabsorption in DCT instead of TAL. In addition, Uscl/Ucre, instead of serum sclerostin, was significantly associated with FeMg. It is plausible that compared with its systemic effect, the local effect of sclerostin, most likely acting via urinary luminal side, plays a more important role in mediating Mg reabsorption in DCT. On DCT, sclerostin may either directly influence apical TRPM6, Kv1.1, or even sodium-chloride cotransporter activity or indirectly affect Mg reabsorption via possible interaction between intracellular Wnt signaling transduction pathway and protein kinase A, phospholipase C, or protein kinase C. The possible role of sclerostin in renal Mg handling in DCT was summarized in Figure 2. However, currently no evidence has demonstrated the molecular mechanism by which sclerostin acts on renal tubules.

Fig. 2.

A simplified diagram illustrating the possible role of sclerostin in renal Mg handling in DCT especially in T2DM with or without CKD. On the apical membrane of DCT, the voltage-gated potassium channel Kv1.1 facilitates Mg entry into cells via melastatin-related TRPM6 by creating polarization of apical membrane. In addition, inhibition of NCC activity, such as thiazides, leads to renal Mg wasting possibly by downregulation of TRPM6. On the basolateral side of DCT, binding of EGF to its receptor EGFR can increase the activation and surface expression of TRPM6. Besides, peptide hormones such as PTH, calcitonin, glucagon, and even vasopressin can regulate Mg reabsorption partly by stimulation of cAMP release and activation of PKA as well as activation of PLC and then PKC. In patients with T2DM with or without CKD, sclerostin may reach the urinary luminal side of DCT and then either directly influences apical TRPM6, Kv1.1, or even NCC activity or indirectly affect Mg reabsorption via possible interaction between intracellular Wnt signaling transduction pathway and PKA, PLC, or PKC. Mg, magnesium; T2DM, type 2 diabetes mellitus; CKD, chronic kidney disease; PTH, parathyroid hormone; DCTs, distal convoluted tubules; NCC, sodium-chloride cotransporter; TRPM6, transient receptor potential cation channel 6; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PLC, phospholipase C; PKC, protein kinase C.

Fig. 2.

A simplified diagram illustrating the possible role of sclerostin in renal Mg handling in DCT especially in T2DM with or without CKD. On the apical membrane of DCT, the voltage-gated potassium channel Kv1.1 facilitates Mg entry into cells via melastatin-related TRPM6 by creating polarization of apical membrane. In addition, inhibition of NCC activity, such as thiazides, leads to renal Mg wasting possibly by downregulation of TRPM6. On the basolateral side of DCT, binding of EGF to its receptor EGFR can increase the activation and surface expression of TRPM6. Besides, peptide hormones such as PTH, calcitonin, glucagon, and even vasopressin can regulate Mg reabsorption partly by stimulation of cAMP release and activation of PKA as well as activation of PLC and then PKC. In patients with T2DM with or without CKD, sclerostin may reach the urinary luminal side of DCT and then either directly influences apical TRPM6, Kv1.1, or even NCC activity or indirectly affect Mg reabsorption via possible interaction between intracellular Wnt signaling transduction pathway and PKA, PLC, or PKC. Mg, magnesium; T2DM, type 2 diabetes mellitus; CKD, chronic kidney disease; PTH, parathyroid hormone; DCTs, distal convoluted tubules; NCC, sodium-chloride cotransporter; TRPM6, transient receptor potential cation channel 6; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PLC, phospholipase C; PKC, protein kinase C.

Close modal

This study has some limitations. First, our study population was restricted to T2DM with uneven distribution of CKD stages. In addition, the number of our study population was relatively small. Nevertheless, repeated measurement analysis was utilized in this study to overcome the limitation of small sample size. Fortunately, we still discovered the interesting association between urinary sclerostin and FeMg. But further studies are needed to scrutinize this association in other populations. Besides, the mechanisms for sclerostin in regulating Mg reabsorption in DCT are also necessary to be explored.

In conclusion, this is the first study to show that in T2DM patients without or with CKD, serum sclerostin was inversely associated with renal Ca excretion. On the other hand, urinary sclerostin was positively associated with renal Mg excretion. Our findings seem to extend not only the role of sclerostin from serum to urine, but also its impacts from bone homeostasis to renal handling of minerals.

The authors would like to thank technical assistance of Chiu-Ya Liao and Ching-Cheng Wang.

Written informed consent was obtained from patients enrolled. The study was approved by the Institution Review Board of E-Da Hospital (number EMRP-104-045) and was in adherence with the Declaration of Helsinki.

The authors have no conflicts of interest to declare.

This study was supported by E-Da Hospital, E-Da Cancer Hospital, and I-Shou University (project EDAHP105008, EDPJ106052, EDCHP107006, and ISU-106-IUC-10).

Concept and design of study: C.F. Wu, H.H. Liou, and S.Y. Hung. Acquisition of data: C.F. Wu, M.Y. Chang, Y.C. Lee, S.Y. Hung, and T.M. Lin. Statistical analysis of data: C.C. Kuo and M.H. Tsai. Drafting manuscript: C.F. Wu. Revising manuscript critically: H.H. Liou.

1.
Compton
JT
,
Lee
FY
.
A review of osteocyte function and the emerging importance of sclerostin
.
J Bone Joint Surg Am
.
2014 Oct 1
;
96
(
19
):
1659
68
. .
2.
Honasoge
M
,
Rao
AD
,
Rao
SD
.
Sclerostin: recent advances and clinical implications
.
Curr Opin Endocrinol Diabetes Obes
.
2014 Dec
;
21
(
6
):
437
46
. .
3.
Baek
K
,
Hwang
HR
,
Park
HJ
,
Kwon
A
,
Qadir
AS
,
Ko
SH
,
TNF-α upregulates sclerostin expression in obese mice fed a high-fat diet
.
J Cell Physiol
.
2014 May
;
229
(
5
):
640
50
. .
4.
Kang
J
,
Boonanantanasarn
K
,
Baek
K
,
Woo
KM
,
Ryoo
HM
,
Baek
JH
,
Hyperglycemia increases the expression levels of sclerostin in a reactive oxygen species- and tumor necrosis factor-alpha-dependent manner
.
J Periodontal Implant Sci
.
2015 Jun
;
45
(
3
):
101
10
. .
5.
Tanaka
K
,
Yamaguchi
T
,
Kanazawa
I
,
Sugimoto
T
.
Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells
.
Biochem Biophys Res Commun
.
2015 May 29
;
461
(
2
):
193
9
. .
6.
Wang
N
,
Xue
P
,
Wu
X
,
Ma
J
,
Wang
Y
,
Li
Y
.
Role of sclerostin and dkk1 in bone remodeling in type 2 diabetic patients
.
Endocr Res
.
2018
;
43
(
1
):
29
38
. .
7.
Cejka
D
,
Marculescu
R
,
Kozakowski
N
,
Plischke
M
,
Reiter
T
,
Gessl
A
,
Renal elimination of sclerostin increases with declining kidney function
.
J Clin Endocrinol Metab
.
2014 Jan
;
99
(
1
):
248
55
. .
8.
Cejka
D
,
Herberth
J
,
Branscum
AJ
,
Fardo
DW
,
Monier-Faugere
MC
,
Diarra
D
,
Sclerostin and Dickkopf-1 in renal osteodystrophy
.
Clin J Am Soc Nephrol
.
2011 Apr
;
6
(
4
):
877
82
. .
9.
Ishimura
E
,
Okuno
S
,
Ichii
M
,
Norimine
K
,
Yamakawa
T
,
Shoji
S
,
Relationship between serum sclerostin, bone metabolism markers, and bone mineral density in maintenance hemodialysis patients
.
J Clin Endocrinol Metab
.
2014 Nov
;
99
(
11
):
4315
20
. .
10.
Kuo
TH
,
Lin
WH
,
Chao
JY
,
Wu
AB
,
Tseng
CC
,
Chang
YT
,
Serum sclerostin levels are positively related to bone mineral density in peritoneal dialysis patients: a cross-sectional study
.
BMC Nephrol
.
2019 Jul 17
;
20
(
1
):
266
. .
11.
Hsu
BG
,
Liou
HH
,
Lee
CJ
,
Chen
YC
,
Ho
GJ
,
Lee
MC
.
Serum sclerostin as an independent marker of peripheral arterial stiffness in renal transplantation recipients: a cross-sectional study
.
Medicine
.
2016 Apr
;
95
(
15
):
e3300
. .
12.
Yang
CY
,
Chang
ZF
,
Chau
YP
,
Chen
A
,
Yang
WC
,
Yang
AH
,
Circulating Wnt/β-catenin signalling inhibitors and uraemic vascular calcifications
.
Nephrol Dial Transplant
.
2015 Aug
;
30
(
8
):
1356
63
. .
13.
Evenepoel
P
,
D'Haese
P
,
Brandenburg
V
.
Sclerostin and DKK1: new players in renal bone and vascular disease
.
Kidney Int
.
2015 Aug
;
88
(
2
):
235
40
. .
14.
Lee
CT
,
Lien
YH
,
Lai
LW
,
Chen
JB
,
Lin
CR
,
Chen
HC
.
Increased renal calcium and magnesium transporter abundance in streptozotocin-induced diabetes mellitus
.
Kidney Int
.
2006 May
;
69
(
10
):
1786
91
. .
15.
Asai
O
,
Nakatani
K
,
Tanaka
T
,
Sakan
H
,
Imura
A
,
Yoshimoto
S
,
Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion
.
Kidney Int
.
2012 Mar
;
81
(
6
):
539
47
. .
16.
Chen
H
,
Li
X
,
Yue
R
,
Ren
X
,
Zhang
X
,
Ni
A
.
The effects of diabetes mellitus and diabetic nephropathy on bone and mineral metabolism in T2DM patients
.
Diabetes Res Clin Pract
.
2013 May
;
100
(
2
):
272
6
. .
17.
Viaene
L
,
Meijers
BK
,
Vanrenterghem
Y
,
Evenepoel
P
.
Evidence in favor of a severely impaired net intestinal calcium absorption in patients with (early-stage) chronic kidney disease
.
Am J Nephrol
.
2012
;
35
(
5
):
434
41
. .
18.
Cozzolino
M
,
Ciceri
P
,
Volpi
EM
,
Olivi
L
,
Messa
PG
.
Pathophysiology of calcium and phosphate metabolism impairment in chronic kidney disease
.
Blood Purif
.
2009
;
27
(
4
):
338
44
. .
19.
Tabibzadeh
N
,
Mentaverri
R
,
Daroux
M
,
Mesbah
R
,
Delpierre
A
,
Paul
JG
,
Differential determinants of tubular phosphate reabsorption: insights on renal excretion of phosphates in kidney disease
.
Am J Nephrol
.
2018
;
47
(
5
):
300
3
. .
20.
Molony
DA
,
Stephens
BW
.
Derangements in phosphate metabolism in chronic kidney diseases/endstage renal disease: therapeutic considerations
.
Adv Chronic Kidney Dis
.
2011 Mar
;
18
(
2
):
120
31
. .
21.
Ryan
ZC
,
Ketha
H
,
McNulty
MS
,
McGee-Lawrence
M
,
Craig
TA
,
Grande
JP
,
Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium
.
Proc Natl Acad Sci U S A
.
2013 Apr 9
;
110
(
15
):
6199
204
. .
22.
Rowe
PS
.
Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway
.
Crit Rev Eukaryot Gene Expr
.
2012
;
22
(
1
):
61
86
. .
23.
Blaine
J
,
Chonchol
M
,
Levi
M
.
Renal control of calcium, phosphate, and magnesium homeostasis
.
Clin J Am Soc Nephrol
.
2015 Jul 7
;
10
(
7
):
1257
72
. .
24.
Cunningham
J
,
Rodríguez
M
,
Messa
P
.
Magnesium in chronic kidney disease Stages 3 and 4 and in dialysis patients
.
Clin Kidney J
.
2012 Feb
;
5
(
Suppl 1
):
i39
51
. .
25.
Pham
PC
,
Pham
PM
,
Pham
SV
,
Miller
JM
,
Pham
PT
.
Hypomagnesemia in patients with type 2 diabetes
.
Clin J Am Soc Nephrol
.
2007 Mar
;
2
(
2
):
366
73
. .
26.
Anwana
AB
,
Garland
HO
.
Renal calcium and magnesium handling in experimental diabetes mellitus in the rat
.
Acta Endocrinol
.
1990 Apr
;
122
(
4
):
479
86
. .
27.
Kumar
R
,
Vallon
V
.
Reduced renal calcium excretion in the absence of sclerostin expression: evidence for a novel calcium-regulating bone kidney axis
.
J Am Soc Nephrol
.
2014 Oct
;
25
(
10
):
2159
68
. .
28.
Curry
JN
,
Yu
ASL
.
Magnesium handling in the kidney
.
Adv Chronic Kidney Dis
.
2018 May
;
25
(
3
):
236
43
. .
29.
Nijenhuis
T
,
Vallon
V
,
van der Kemp
AW
,
Loffing
J
,
Hoenderop
JG
,
Bindels
RJ
.
Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia
.
J Clin Invest
.
2005 Jun
;
115
(
6
):
1651
8
. .
30.
Dai
LJ
,
Ritchie
G
,
Kerstan
D
,
Kang
HS
,
Cole
DE
,
Quamme
GA
.
Magnesium transport in the renal distal convoluted tubule
.
Physiol Rev
.
2001 Jan
;
81
(
1
):
51
84
. .

Additional information

Ching-Fang Wu and Hung-Hsiang Liou contributed equally to this work.

Open Access License / Drug Dosage / Disclaimer
This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.