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1.  Outcome predictability of serum alkaline phosphatase in men with pre-dialysis CKD 
Nephrology Dialysis Transplantation  2010;25(9):3003-3011.
Background. Serum alkaline phosphatase (ALP) increases in patients with chronic kidney disease (CKD) and high-turnover bone disease. ALP may represent an adjunct marker of high bone turnover devoid of drawbacks of serum parathyroid hormone (PTH), and it may also be associated with cardiovascular calcification in CKD. Higher ALP has been recently associated with increased mortality and coronary calcification in dialysis patients. In pre-dialysis CKD patients, this association is not clear.
Methods. We examined the association of baseline, time-varying and time-averaged ALP with all-cause mortality and the composite of pre-dialysis mortality or end-stage renal disease in a historical prospective cohort of 1158 male veterans with pre-dialysis CKD from a single institution by using multivariable-adjusted Cox models.
Results. Higher ALP was associated with increased mortality irrespective of the statistical model. Time-averaged ALP displayed a consistent linear association with mortality: a 50-U/L higher serum ALP was associated with a multivariable-adjusted death hazard ratio (95% confidence interval) of 1.17 (1.08–1.28), P < 0.001. Baseline and time-varying ALP showed non-linear associations with mortality, with serum levels above 70 U/L in all models and with lower levels in time-varying models. Associations between ALP levels and the composite outcomes were similar. However, compared to serum PTH, mortality predictability of ALP appeared more incremental.
Conclusions. Elevated ALP is associated with increased mortality in patients with pre-dialysis CKD. Low ALP appears to be associated with short-term mortality.
doi:10.1093/ndt/gfq144
PMCID: PMC2948834  PMID: 20299338
alkaline phosphatase; chronic kidney disease; mortality
2.  Applicability of fibroblast growth factor 23 for evaluation of risk of vertebral fracture and chronic kidney disease-mineral bone disease in elderly chronic kidney disease patients 
BMC Nephrology  2012;13:122.
Background
Elderly patients with chronic kidney disease (CKD) are usually at a high risk of fractures due to both osteoporosis and CKD-mineral bone disease (MBD). A new marker is needed to prevent fractures and control CKD-MBD from the early to advanced stages of CKD. In the early stage of CKD, fibroblast growth factor 23 (FGF23) level increases before parathyroid hormone (PTH) and phosphate levels increase, and steadily increases with the progression of kidney disease. It has been reported that FGF23 is related to the overall fracture risk. We investigated the usefulness of FGF23 as a marker for evaluating the risk of vertebral fracture and CKD-MBD in elderly CKD patients.
Methods
One hundred and five elderly predialysis CKD patients who had never been treated for osteoporosis and had never used calcium supplements, vitamin D supplements, or phosphate binders were enrolled in this cross-sectional study in Tokyo, Japan. We investigated the prevalence of vertebral fracture and measured serum calcium, phosphate, 1,25(OH)2 vitamin D [1,25(OH)2D], intact PTH, FGF23, alkaline phosphatase, and urinary N-terminal telopeptide levels. Then, we examined the relationship between the level of FGF23 and those of bone-metabolism-related markers and identified markers associated with vertebral fractures in elderly CKD patients.
Results
The background features of the patients were as follows: female, 32.4%; diabetes mellitus, 39.0%; average age (standard deviation), 73.2 (7.7) years; and estimated glomerular filtration rate (eGFR), 45.7 (24.1) ml/min/1.73 m2. Adjusted multivariate regression analysis showed that the natural logarithm value of FGF23 level [ln(FGF23)] was positively associated with body mass index (p = 0.002), serum phosphate level (p = 0.0001), and negatively with eGFR (p = 0.0006). Multivariate logistic regression analysis showed that vertebral fracture was independently associated with ln(FGF23) (adjusted odds ratio, 4.44; 95% confidence interval, 1.13-17.46). A receiver-operating-characteristic curve of ln(FGF23) showed that the optimal cutoff level of FGF23 indicative of vertebral fracture was 56.8 pg/ml (sensitivity, 0.82; specificity, 0.63).
Conclusions
FGF23 level was independently associated with the levels of bone-metabolism-related markers and vertebral fracture. FGF23 is a new candidate marker for detecting abnormalities of bone metabolism and vertebral fracture in elderly CKD patients.
doi:10.1186/1471-2369-13-122
PMCID: PMC3506497  PMID: 23013306
CKD; Fracture; FGF23; CKD-MBD; Phosphate; PTH; Geriatrics
3.  Effects of paricalcitol on calcium and phosphate metabolism and markers of bone health in patients with diabetic nephropathy: results of the VITAL study 
Nephrology Dialysis Transplantation  2013;28(9):2260-2268.
Background
Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium–phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant risks of cardiovascular and bone disorders. Active vitamin D can suppress parathyroid hormone (PTH), but may raise serum calcium and phosphate concentrations. Paricalcitol, a selective vitamin D activator, suppressed PTH in CKD patients (stages 3 and 4) with secondary hyperparathyroidism (SHPT) with minimal changes in calcium and phosphate metabolism.
Methods
The VITAL study enrolled patients with CKD stages 2–4. We examined the effect and relationship of paricalcitol to calcium and phosphate metabolism and bone markers in a post hoc analysis of VITAL. The study comprised patients with diabetic nephropathy enrolled in a double-blind, placebo-controlled, randomized trial of paricalcitol (1 or 2 μg/day). Urinary and serum calcium and phosphate, serum BAP, and intact PTH (iPTH) concentrations were measured throughout the study.
Results
Baseline demographics and calcium, phosphate, PTH (49% with iPTH <70 pg/mL), and BAP concentrations were similar between groups. A transient, modest yet significant increase in phosphate was observed for paricalcitol 2 μg/day (+0.29 mg/dL; P < 0.001). Dose-dependent increases in serum and urinary calcium were observed; however, there were few cases of hypercalcemia: one in the 1-μg/day group (1.1%) and three in the 2-μg/day group (3.2%). Significant reductions in BAP were observed that persisted for 60 days after paricalcitol discontinuation (P < 0.001 for combined paricalcitol groups versus placebo). Paricalcitol dose-dependent reductions in iPTH were observed. Paricalcitol in CKD patients (±SHPT) was associated with modest increases in calcium and phosphate.
Conclusion
Paricalcitol reduces BAP levels, which may be beneficial for reducing vascular calcification.
Trial registration
Trial is registered with ClinicalTrials.gov, number NCT00421733.
doi:10.1093/ndt/gft227
PMCID: PMC3769981  PMID: 23787544
bone-specific alkaline phosphatase; calcitriol; hypercalcemia; hyperphosphatemia; paricalcitol; vitamin D receptor activation
4.  The high prevalence of chronic kidney disease-mineral bone disorders: A hospital-based cross-sectional study 
Indian Journal of Nephrology  2012;22(4):285-291.
Mineral bone disorder (MBD) is an important complication of chronic kidney disease (CKD). However, there are limited data on the pattern of MBD in Indian CKD population. The aim of this study was to describe spectrum of MBD in patients with CKD in our center. This was a hospital-based cross-sectional observational study. Patients with stage 4 and 5 CKD were included in this study. Those receiving calcium supplement, vitamin D or its analogues, and calcimimetic were excluded. Serum/plasma levels of creatinine, albumin, calcium, phosphate, total alkaline phosphatase (TAP), intact parathormone (iPTH), and 25-OH vitaminD (25-vitD) were measured. Radiological survey of bones was carried out in all cases, and echocardiography done in selected patients. Statistical analysis was done using Sigmaplot 10.0 software. A total of 150 patients (114 males, 36 females) were included in this study. Mean age was 45.67±16.96 years. CKD stage 4 and 5D were found in 26% (n=39) and 74% (n=111) of study population, respectively. The most common underlying native kidney diseases in patients of CKD 4 and 5D were diabetic nephropathy (41.03%) and CGN (41.44%), respectively. Median (first quartile, third quartile) values for serum levels of corrected calcium (cCa), phosphate, cCaXPO4 product, TAP, plasma iPTH, and 25-vitD in stage 4 CKD were 8.36 (7.79, 8.91) mg/dL, 4.9 (3.92, 6.4) mg/dL, 41.11 (34.01, 53.81) mg2/dL2, 97 (76.5, 184.25) IU/L, 231 (124.5, 430.75) pg/mL, and 12 (6.98, 23.55) ng/mL, respectively; and in stage 5D CKD were 8.36 (7.66, 8.95) mg/dL, 5.7 (4.23, 6.95) mg/dL, 46.5 (37.16, 54.47) mg2/dL2, 180 (114.5, 276.25) IU/L, 288 (169.75, 625.0) pg/mL, and 18.4 (10.0, 26.4) ng/mL, respectively. Prevalence of hypocalcemia (56.41% vs. 54.95%), hyperphosphatemia (64.10% vs. 70.27%), and hyperparathyroidism (84.62% vs. 88.29%) was not different between patients with CKD 4 and 5D. However, iPTH level outside the target range and increased TAP level were significantly (P<0.001) more common in CKD stage 5D. Multiple logistic regression analysis for hyperparathyroidism revealed significant inverse correlation with cCa in CKD 5D. There were no significant differences in vitamin D status and prevalence of valvular calcification between CKD stage 4 and 5D. X-ray revealed renal osteodystrophy in 8 (5.33%) patients, while it was normal in 118 (78.67%) patients. Secondary hyperparathyroidism, hyperphosphatemia, hypocalcemia, increased TAP, and 25-OH vitamin D deficiency and insufficiency were quite common in CKD 4 and 5 patients. The commonest type of MBD in CKD 4 and 5D was secondary hyperparathyroidism.
doi:10.4103/0971-4065.101249
PMCID: PMC3495351  PMID: 23162273
Chronic kidney disease; hyperparathyroidism; hyperphosphatemia; hypocalcemia; mineral bone disorder
5.  Profile of incident chronic kidney disease related-mineral bone disorders in chronic kidney disease Stage 4 and 5: A hospital based cross-sectional survey 
Indian Journal of Nephrology  2014;24(2):97-107.
Chronic kidney disease related-mineral bone disorder (CKD-MBD) has been poorly studied in pre-dialysis Indian CKD patients. We aimed to study the clinical, biochemical and extra skeletal manifestations of untreated CKD-MBD in pre-dialysis Stage 4 and 5 CKD patients attending nephrology out-patient clinic at a tertiary care hospital in South India. A hospital based cross-sectional survey including, demographic profile, history of CKD-MBD symptoms, measurement of serum calcium, phosphate, parathyroid hormone, 25 hydroxy vitamin D (25(OH) D) and alkaline phosphatase; lateral abdominal X-rays for abdominal aortic calcification (AAC) and echocardiography for valvular calcification (VC) was carried out. Of the 710 patients surveyed, 45% had no CKD-MBD related symptom. Prevalence of hypocalcemia, hyperphosphatemia, hyperparathyroidism (>150 pg/mL) and 25(OH) D levels <30 ng/mL was 66.3%, 59%, 89.3% and 74.7% respectively. Echocardiography was carried out in 471 patients; 96% of whom had VC (calcification score ≥1). Patients with VC were older and had lower 25(OH) D levels than those without. Lateral abdominal X-rays were obtained in 558 patients, 6.8% of whom were found to have AAC, which was associated with older age. Indian patients with incident CKD-MBD have a high prevalence of hypocalcemia, 25(OH) D deficiency and VC even prior to initiating dialysis while AAC does not appear to be common. The association between 25(OH) D deficiency and VC needs further exploration.
doi:10.4103/0971-4065.127897
PMCID: PMC3968617
Aortic calcification; chronic kidney disease related mineral bone disorder; pre-dialysis chronic kidney disease; valvular calcification; vitamin D
6.  The link between bone and coronary calcifications in CKD-5 patients on haemodialysis 
Nephrology Dialysis Transplantation  2010;26(3):1010-1015.
Background. Vascular calcifications are frequent in Stage 5 chronic kidney disease (CKD-5) patients receiving haemodialysis. The current study was designed to evaluate the associations between bone turnover/volume and coronary artery calcifications (CAC).
Methods. In 207 CKD-5 patients, bone biopsies, multislice computed tomography of the coronary arteries and blood drawings for relevant biochemical parameters were done. The large number of CKD-5 patients enrolled allowed separate evaluation of patients with CAC versus patients without CAC and adjustment for traditional and non-traditional risk factors for CAC.
Results. When all patients were analysed, associations were found between CAC and bone turnover, bone volume, age, gender and dialysis vintage. When only patients with CAC were included, there was a U-shaped relationship between CAC and bone turnover, whilst the association with bone volume was lost. In these patients, the relationship of CAC with age, gender and dialysis vintage remained.
Conclusions. Beyond the non-modifiable risk factors of age, gender and dialysis vintage, these data show that bone abnormalities of renal osteodystrophy amenable to treatment should be considered in the management of patients with CAC.
doi:10.1093/ndt/gfq491
PMCID: PMC3108347  PMID: 20709740
bone turnover; bone volume; coronary calcifications; dialysis; renal osteodystrophy
7.  Insights into Nutritional and Inflammatory Aspects of Low Parathyroid Hormone in Dialysis Patients 
In people with advanced chronic kidney disease (CKD), secondary hyperparathyroidism is associated with high-turnover bone disease. A low serum PTH may not necessarily be due to hypodynamic bone but another facet of the malnutrition-inflammation cachexia-syndrome (MICS). A recent 5-year cohort study in 748 stable hemodialysis outpatients showed that after removing the confounding by the MICS, the moderately low PTH in 100 to 150 p/ml range was associated with the greatest survival. Survival data from Japanese dialysis patients show similar survival advantages of lower PTH range. Low serum PTH appears associated with markers of protein-energy wasting and inflammation, and this association may confound the relationship between serum PTH and alkaline phosphatase. PTH stimulates lipogenesis through influx of calcium into the adipocytes. PTH secretion is suppressed by interleukin-1 beta and interleukin-6, which are pro-inflammatory cytokines associated with poor outcome in dialysis patients. These cytokines inhibits PTH secretion in cultured parathyroid tissue slices. In this article we review the association of a low serum PTH with the MICS in CKD patients and suggest avoiding over-interpretation of low serum PTH as an indicator of low-turnover bone disease.
doi:10.1053/j.jrn.2010.10.006
PMCID: PMC3032422  PMID: 21195929
Parathyroid hormone (PTH); adynamic bone disease; malnutrition-inflammation complex; alkaline phosphatase; cytokines
8.  Association of serum alkaline phosphatase with mortality in non-selected European patients with CKD5D: an observational, three-centre survival analysis 
BMJ Open  2014;4(2):e004275.
Objectives
For characterisation of mineral bone disease in chronic kidney disease (CKD), laboratory surrogates have been suggested. This observational should investigate the association of total and skeletal alkaline phosphatase (AP) with mortality of patients undergoing maintenance renal replacement therapy.
Setting
Three renal outpatient centers in eastern-central Germany (secondary and tertiary care).
Participants
Complete survival and laboratory datasets were available in 407 of 493 patients. Age and gender distribution was equivalent to a general population with end-stage CKD (CKD5D). Patients were included between 2008 and 2010 if at least 2 weeks of maintenance treatment were documented.
Primary outcome measures
Mortality was estimated by setting the end of dialysis date as event date. Events other than death (change to another centre, life-sustaining renal function or transplantation) were censored.
Results
The OR to die within follow-up for patients in the higher of two total AP strata was 2.70 (95% CI 1.76 to 4.15). In univariate Kaplan-Meier analysis, total AP had a strong association with all-cause mortality (LogRank=24.1, p<0.001). Mean total AP and individual lowest skeletal AP, but not mean skeletal AP entered step-wise Cox models for survival from dialysis start (χ2=22.4; p<0.001) after adjusting for age, Kt/V, diabetes and vintage. Mean values of skeletal, total AP and parathyroid hormone were 14.8±8.9 µg/L, 91.9±55.3 U/L and 188±164 ng/L, respectively. Skeletal and total AP were highly correlated (R=0.86; p<0.001).
Conclusions
This unselected CKD5D population exhibited a clinical significant association of total AP with crude mortality and a stronger death risk association of total AP and individual lowest skeletal AP with crude mortality.
doi:10.1136/bmjopen-2013-004275
PMCID: PMC3939663  PMID: 24578540
Statistics & Research Methods
9.  Characterization of Mandibular Bone in a Mouse Model of Chronic Kidney Disease 
Journal of periodontology  2010;81(2):300-309.
Background
Chronic kidney disease (CKD) is a worldwide health problem with increasing prevalence and poor outcomes including severe cardiovascular disease and renal osteodystrophy. With advances in medical treatment, CKD patients are living longer and require oral care. The aim of this study was to determine the effects of CKD and dietary phosphate on mandibular bone structure using a uremic mouse model.
Methods
Uremia (U) was induced in female DBA/2 mice by partial renal ablation. Uremic mice received either a normal phosphate (NP) or a high phosphate (HP) diet. Sham surgeries were performed in a control group of mice, and half received either a NP or a HP diet. At termination, animals were sacrificed and mandibles collected for microcomputed tomography (micro-CT) and histological analysis.
Results
Sera levels of BUN, PTH and alkaline phosphatase were all significantly increased in U/NP and U/HP vs. Sham controls, while serum calcium was increased in the U/HP group and no differences were noted in serum phosphate levels between groups. Micro-CT analyses revealed a significant reduction in cortical bone thickness and an increase in trabecular thickness and trabecular bone volume/tissue volume in U/NP and U/HP groups compared to Sham/NP. A significant reduction in cortical bone thickness was also found in the Sham/HP vs. Sham/NP group. Histological evaluation confirmed increased trabeculation in the U groups.
Conclusions
CKD in mice, especially under conditions of high phosphate feeding, results in marked effects on alveolar bone homeostasis.
doi:10.1902/jop.2009.090379
PMCID: PMC2862731  PMID: 20151810
Bone biology; periodontal-systemic disease interactions; risk factor(s)
10.  Upregulation of Inflammatory Genes and Downregulation of Sclerostin Gene Expression Are Key Elements in the Early Phase of Fragility Fracture Healing 
PLoS ONE  2011;6(2):e16947.
Background
Fracture healing is orchestrated by a specific set of events that culminates in the repair of bone and reachievement of its biomechanical properties. The aim of our work was to study the sequence of gene expression events involved in inflammation and bone remodeling occurring in the early phases of callus formation in osteoporotic patients.
Methodology/Principal Findings
Fifty-six patients submitted to hip replacement surgery after a low-energy hip fracture were enrolled in this study. The patients were grouped according to the time interval between fracture and surgery: bone collected within 3 days after fracture (n = 13); between the 4th and 7th day (n = 33); and after one week from the fracture (n = 10). Inflammation- and bone metabolism-related genes were assessed at the fracture site. The expression of pro-inflammatory cytokines was increased in the first days after fracture. The genes responsible for bone formation and resorption were upregulated one week after fracture. The increase in RANKL expression occurred just before that, between the 4th–7th days after fracture. Sclerostin expression diminished during the first days after fracture.
Conclusions
The expression of inflammation-related genes, especially IL-6, is highest at the very first days after fracture but from day 4 onwards there is a shift towards bone remodeling genes, suggesting that the inflammatory phase triggers bone healing. We propose that an initial inflammatory stimulus and a decrease in sclerostin-related effects are the key components in fracture healing. In osteoporotic patients, cellular machinery seems to adequately react to the inflammatory stimulus, therefore local promotion of these events might constitute a promising medical intervention to accelerate fracture healing.
doi:10.1371/journal.pone.0016947
PMCID: PMC3037947  PMID: 21347301
11.  Osteo-Renal Regulation of Systemic Phosphate Metabolism 
IUBMB life  2011;63(4):240-247.
Summary
Impaired kidney function and subsequent skeletal responses play a critical role in disrupting phosphate balance in chronic kidney disease (CKD) patients with mineral and bone disorder (CKD-MBD). In patients with CKD-MBD, the inability of the kidney to maintain normal mineral ion balance affects bone remodeling to induce skeletal fracture and extraskeletal vascular calcification. In physiological conditions, bone-derived fibroblast growth factor 23 (FGF23) acts on the kidney to reduce serum phosphate and 1,25-dihydroxyvitamin D levels. In humans, increased bioactivity of FGF23 leads to increased urinary phosphate excretion, which induces hypophosphatemic diseases (e.g., rickets/osteomalacia). However, reduced FGF23 activity is associated with hyperphosphatemic diseases (e.g., tumoral calcinosis). In patients with CKD, high serum levels of FGF23 fail to reduce serum phosphate levels and lead to numerous complications, including vascular calcification, one of the important determinants of mortality of CKD-MBD patients. Of particular significance, molecular, biochemical and morphological changes in patients with CKD-MBD are mostly due to osteo-renal dysregulation of mineral ion metabolism. Furthermore, hyperphosphatemia can partly contribute to the development of secondary hyperparathyroidism in patients with CKD-MBD. Relatively new pharmacological agents including sevelamer hydrochloride, calcitriol analogs and cinacalcet hydrochloride are used either alone, or in combination, to minimize hyperphosphatemia and hyperparathyroidism associated complications to improve morbidity and mortality of CKD-MBD patients. This article will briefly summarize how osteo-renal miscommunication can induce phosphate toxicity, resulting in extensive tissue injuries.
doi:10.1002/iub.437
PMCID: PMC3120048  PMID: 21438115
Klotho; fibroblast growth factor 23; vitamin D; parathyroid hormone; chronic kidney disease
12.  PATTERNS OF FGF-23, DMP1 AND MEPE EXPRESSION IN PATIENTS WITH CHRONIC KIDNEY DISEASE 
Bone  2009;45(6):1161-1168.
Fibroblast growth factor 23 (FGF-23), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) are skeletal proteins involved in the regulation of phosphate homeostasis and bone metabolism. Circulating FGF-23 levels are increased in patients with chronic kidney disease (CKD); however, FGF-23 skeletal expression and its regulation by DMP1 and MEPE have yet to be evaluated. Thus, expression of these three proteins was characterized by immunohistochemistry in 32 pediatric and young adult patients with CKD stages 2–5. When compared to normal controls, bone FGF-23 and DMP1 expression were increased in all stages of CKD; significant differences in bone FGF-23 and DMP1 expression were not detected between pre-dialysis CKD and dialysis patients. Bone MEPE expression in CKD did not differ from controls. FGF-23 was expressed in osteocyte cell bodies located at the trabecular periphery. DMP1 was widely expressed in osteocyte cell bodies and dendrites throughout bone. MEPE was also expressed throughout bone, but only in osteocyte cell bodies. Bone FGF-23 expression correlated directly with plasma levels of the protein (r=0.43, p<0.01) and with bone DMP1 expression (r=0.54, p<0.01) and expression of both proteins were inversely related to osteoid accumulation. Bone MEPE expression was inversely related to bone volume. In conclusion, skeletal FGF-23 and DMP1 expression are increased in CKD and are related to skeletal mineralization. The patterns of expression of FGF-23, MEPE, and DMP1 differ markedly in trabecular bone, suggesting that individual osteocytes may have specialized functions. Increases in bone FGF-23 and DMP1 expression suggest that osteocyte function is altered early in the course of CKD.
doi:10.1016/j.bone.2009.08.008
PMCID: PMC2783834  PMID: 19679205
13.  Cardiovascular risk markers associated with arterial calcification in patients with chronic kidney disease Stages 3 and 4 
Clinical Kidney Journal  2014;7(2):167-173.
Background
The contribution of pro-inflammatory markers to cardiovascular (CV) risk and vascular calcification in chronic kidney disease (CKD) remains largely to be elucidated. We investigated the association between plasma levels of several biomarkers and calcification volume in three different vascular beds in CKD Stages 3 and 4 patients.
Methods
This is a cross-sectional, exploratory study in patients with an estimated glomerular filtration rate (eGFR) ≥20 and ≤45 mL/min/1.73 m2 and serum phosphorus ≥3.5 and <6.0 mg/dL enrolled in a previously published randomized, double blind, placebo-controlled single-centre trial. Ethylenediaminetetraacetic acid (EDTA) plasma samples were collected at baseline before patients received study medication and analysed for the presence of a number of biomarkers. Coronary artery calcium (CAC), thoracic aortic calcification (TAC) and abdominal aortic calcification (AAC) volumes were measured using standard electron-beam computed tomography protocols. Associations were adjusted for age, sex, smoking, body mass index, diabetes mellitus status, low-density lipoprotein cholesterol (LDL-C), systolic blood pressure and eGFR.
Results
Associations with CAC were found for β2-microglobulin (B2M), fibroblast growth factor 23 (FGF23), interleukin-8 (IL-8) and IL-18. AAC was associated with: B2M, FGF23 and IL-2 receptor alpha (IL-2 RA). TAC was associated with: B2M, FGF23, IL-2 RA, IL-18 and tumour necrosis factor receptor type I. For most of the analysed biomarkers, there were non-significant trends of associations with calcification.
Conclusions
This exploratory study found that elevated plasma levels of several inflammatory biomarkers are significantly associated with arterial calcification in CKD Stages 3 and 4 patients. A greater understanding of inflammation and calcification in CKD patients may help the development of CV risk-assessment algorithms for better management of these patients.
doi:10.1093/ckj/sfu017
PMCID: PMC3968563
arterial calcification; biomarkers; cardiovascular risk; chronic kidney disease; inflammation
14.  Changes of serum bone markers in CAPD and hemodialysis patients 
Hippokratia  2007;11(4):199-201.
Background: A non-invasive method for evaluation of high-turnover and low-turnover bone diseases is the measurement of certain important serum bone markers such as osteocalcin, procolagen-I-propeptide, dioxypiridinoline, hydroxyproline and alkaline phosphatase. Renal osteodystrophy (ROD) in pre-dialysis and dialysis patients, is manifested in 3 forms: high-turnover ROD, related to secondary hyperparathyroidism; low-turnover ROD and mixed ROD.
Material and methods: Serum levels of intact parathyroid hormone (iPTH), osteocalcin (OC), procolagen-I-propeptide (PIPC) and dioxypiridinoline (DYP) were measured in 20 patients on hemodialysis (HD) and 20 patients on continuous ambulatory peritoneal dialysis (CAPD) to assess the prevalence of ROD type in the HD and CAPD groups.
Results: We found lower mean levels of all bone markers in CAPD patients, (iPTH: 219±235 vs. 428±285 pg/ml; p<0.01; OC 10.2±7.5 vs. 21.3±7.2 ng/ml; p<0.01; PIPC 111±57.3 vs. 218±62.4 ng/ml; p<0.01; DYP 7.3±6.4 vs. 55.2±23.3nm/l; p<0.001; AP 164±66 vs. 325±188 U/l; p<0.01) and lower than normal in 11 of them and higher than normal PTH, AP and some of the other serum markers (PICP; DYP) in 14 HD patients.
Conclusions: The lower levels of the investigated serum bone markers in CAPD patients suggest that low-turnover ROD prevails in these patients than in HD pts.
PMCID: PMC2552984  PMID: 19582194
serum bone markers; osteocalcin; procolagen-I-propeptide; dioxipyridinoline; hydroxyproline; alkaline phosphatase; intact parathyroid hormone; high-turnover ROD; low-turnover ROD
15.  The bone-vascular axis in chronic kidney disease 
PURPOSE
This review highlights the most recent publications addressing the relationship between bone and vascular calcification in patients with chronic and end-stage kidney disease.
RECENT FINDINGS
The relatively new term “chronic kidney disease - mineral bone disorder” (CKD-MBD) reflects the growing reach of CKD research into the realm of systems physiology, involving a triad of renal, skeletal and vascular tissues. Recent studies address underlying mechanisms of the bone and vascular complications of CKD and point to a variety of biochemical factors, including phosphatonins [fibroblast growth factor-23, matrix-matrix extracellular phosphoglycoprotein], bone morphogenetic protein 7, osteoprotegerin, matrix GLA protein, ectonucleotide pyrophophatase/phosphodiesterase 1, alkaline phosphatase, and lipid oxidation products. Studies also demonstrate that agents used for treatment of one component of the triad often act on the other components of the triad - beneficially or adversely. These findings emphasize the importance of avoiding the subspecialty, single organ viewpoint when treating individual components of CKD-MBD.
SUMMARY
The consistent synchrony among chronic kidney disease, aortic calcification and bone loss offers clues to underlying mechanisms for the systemic abnormalities.
doi:10.1097/MNH.0b013e32833a3d67
PMCID: PMC3001327  PMID: 20508522
Calcification; Vascular; Osteodystrophy; Kidney
16.  Von Willebrand factor, ADAMTS13 activity, TNF-α and their relationships in patients with chronic kidney disease 
Patients with chronic kidney disease (CKD) often exhibit associated endothelial dysfunction and inflammation. Systemic inflammation may contribute to the endothelial dysfunction and accelerated thrombosis observed in CKD patients. In this study, we assessed the relationships among endothelial dysfunction, a disintegrin-like and metalloprotease with thrombospondin type 1 repeats 13 (ADAMTS13) activity and levels of inflammatory cytokines in CKD patients. CKD patients were classified into three groups: The chronic glomerulonephritis group (CGN; n=31), the idiopathic nephritic syndrome group (NS; n=32) and the lupus nephritis group (LN; n=41). We measured the plasma levels of tumor necrosis factor-α (TNF-α), von Willebrand factor (VWF) antigen (VWF:Ag) and ADAMTS13 activity using an ELISA-based method in CKD patients (n=104) and normal controls (n=32). The ratio of the VWF:Ag levels to ADAMTS13 activity was calculated. The VWF:Ag levels were significantly higher and the ADAMTS13 activities were significantly lower in the disease groups compared to the controls (P<0.01). ADAMTS13 activity was lower in the NS group compared to the CGN and LN groups (P<0.05). The TNF-α levels were higher in the CKD group compared to the control group (P<0.01). TNF-α was positively correlated with the VWF:Ag levels (r=0.242, P=0.013) and negatively correlated with the glomerular filtration rate (GFR) (r=−0.193, P=0.049). ADAMTS13 activity was negatively correlated with the cholesterol levels in CKD patients (r=−0.2, P= 0.042). TNF-α levels in CKD were positively correlated with the VWF:Ag levels and negatively correlated with GFR, which indicates that inflammation may be a major cause of endothelial dysfunction and an index of renal function. The VWF:Ag levels increased and ADAMTS13 activity decreased in CKD patients, which indicates that CKD leads to a prothrombotic state.
doi:10.3892/etm.2011.432
PMCID: PMC3438530  PMID: 22969924
tumor necrosis factor-α; von Willebrand factor; ADAMTS13; chronic kidney disease
17.  Fracture Risk Assessment in Chronic Kidney Disease, Prospective Testing Under Real World Environments (FRACTURE): a prospective study 
BMC Nephrology  2010;11:17.
Background
Chronic kidney disease (CKD) is associated with an increased risk of fracture. Decreased bone mass and disruption of microarchitecture occur early in the course of CKD and worsens with the progressive decline in renal function so that at the time of initiation of dialysis at least 50% of patients have had a fracture. Despite the excess fracture risk, and the associated increases in morbidity and mortality, little is known about the factors that are associated with an increase in fracture risk. Our study aims to identify prognostic factors for bone loss and fractures in patients with stages 3 to 5 CKD.
Methods
This prospective study aims to enroll two hundred and sixty men and women with stages 3 to 5 CKD. Subjects will be followed for 24 months and we will examine the ability of: 1) bone mineral density by dual x-ray absorptiometry at the spine, hip, and radius; 2) volumetric bone density by high resolution peripheral quantitated computed tomography at the radius and tibia; 3) serum markers of bone turnover; 4) bone formation rate by bone biopsy; and 5) muscle strength and balance to predict spine and non-spine fractures, identified by self-report and/or vertebral morphometry. All measurements will be obtained at baseline, at 12 and at 24 months with the exception of bone biopsy, which will be measured once at 12 months. Subjects will be contacted every 4 months to determine if there have been incident fractures or falls.
Discussion
This study is one of the first that aims to identify risk factors for fracture in early stage CKD patients. Ultimately, by identifying risk factors for fracture and targeting treatments in this group-before the initiation of renal replacement therapy - we will reduce the burden of disease due to fractures among patients with CKD.
doi:10.1186/1471-2369-11-17
PMCID: PMC2936367  PMID: 20727179
18.  Intact PTH Combined With the PTH Ratio for Diagnosis of Bone Turnover in Dialysis Patients: A Diagnostic Test Study 
Background
Determination of parathyroid hormone (PTH) is the most commonly used surrogate marker for bone turnover in stage 5 chronic kidney disease patients on dialysis (CKD-5D patients). The objective of the current study was to evaluate the predictive value of various PTH measurements for identifying low or high bone turnover rate.
Study design
Diagnostic test study.
Settings & Participants
141 CKD-5D patients from 15 US hemodialysis centers.
Index Tests
Intact PTH, PTH 1–84, and PTH ratio (ratio of level of PTH 1–84 to level of large carboxy-terminal PTH fragments).
Reference Test or Outcome
Bone turnover determined by bone histomorphometry
Other Measurements
Demographic and treatment related factors, serum calcium and phosphorus.
Results
Histologically, patients presented with a broad range of bone turnover abnormalities. In White patients (n=70), the iPTH cut-off of >420 pg/ml resulted in classifying 84% of the patients correctly as high turnover. A PTH ratio <1.0 when added to an intact PTH <420 pg/ml increased the positive predictive value for low bone turnover from 74% to 90% in these patients. In Black patients (n=71), adding a PTH ratio <1.2 to an intact PTH <340pg/ml increased the positive predictive value for low bone turnover from 48% to 90%. Adding a PTH ratio >1.6 to an intact PTH between 340 and 790 pg/ml increased the positive predictive value for high bone turnover from 56% to 71%.
Limitations
Since the research protocol called for carefully controlled blood specimen handling, drawing of blood and routine specimen handling might be less stringent in clinical practice. By limiting study participation to Black and White CKD-5D patients, we cannot comment on the roles of intact PTH, PTH 1–84 and the PTH ratio in other racial/ethnic groups.
Conclusion
In Black CKD-5D patients, addition of the PTH ratio to intact PTH measurements is helpful for diagnosing low and high bone turnover. In White CKD-5D patients, it aids in the diagnosis of low bone turnover.
doi:10.1053/j.ajkd.2009.12.041
PMCID: PMC2882243  PMID: 20347512
19.  Fibroblast growth factor 23 is associated with carotid artery calcification in chronic kidney disease patients not undergoing dialysis: a cross-sectional study 
BMC Nephrology  2013;14:22.
Background
Fibroblast growth factor 23 (FGF23) is an important hormone in the regulation of phosphate metabolism. It is unclear whether FGF23 is associated with carotid artery calcification (CAAC) in predialysis patients. The present study aimed to clarify the relationship between FGF23 and CAAC in patients with chronic kidney disease (CKD) who were not on dialysis.
Methods
One-hundred ninety-five predialysis CKD patients were enrolled in this cross-sectional study. CAAC was assessed using multidetector computed tomography, and the prevalence of CAAC was examined. Intact FGF23 was measured in each patient. The risk factors for CAAC were evaluated using a logistic regression model.
Results
We found CAAC in 66% of the patients. The prevalence of CAAC significantly increased across CKD stages: it was 37% in CKD stages 1–2, 58% in stage 3; 75% in stage 4, and 77% in stage 5 (p < 0.01). In multivariate analysis, smoking, diabetes mellitus and log FGF23 were each identified as risk factors for CAAC. The study population was divided in quartiles of FGF23 levels. Compared with the lowest FGF23 quartile, each subsequent quartile had a progressively higher odds ratio (OR) for CAAC, adjusted for confounders (ORs [95% confidence interval] of 2.34 [0.78 to 7.31], 5.28 [1.56 to 19.5], and 13.6 [2.92 to 74.6] for the second, third, and fourth quartiles, respectively.
Conclusions
The prevalence of CAAC is increased with the decline in the kidney function. FGF23 is independently related to CAAC in patients with CKD who are not on dialysis.
doi:10.1186/1471-2369-14-22
PMCID: PMC3554512  PMID: 23339433
Fibroblast growth factor 23; Vascular calcification; Carotid artery calcification; Chronic kidney disease
20.  Bisphophonates in CKD Patients with Low Bone Mineral Density 
The Scientific World Journal  2013;2013:837573.
Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) have a high risk of bone fracture because of low bone mineral density and poor bone quality. Osteoporosis also features low bone mass, disarranged microarchitecture, and skeletal fragility, and differentiating between osteoporosis and CKD-MBD in low bone mineral density is a challenge and usually achieved by bone biopsy. Bisphosphonates can be safe and beneficial for patients with a glomerular filtration rate of 30 mL/min or higher, but prescribing bisphosphonates in advanced CKD requires caution because of the increased possibility of low bone turnover disorders such as osteomalacia, mixed uremic osteodystrophy, and adynamic bone, even aggravating hyperparathyroidism. Therefore, bone biopsy in advanced CKD is an important consideration before prescribing bisphosphonates. Treatment also may induce hypocalcemia in CKD patients with secondary hyperparathyroidism, but vitamin D supplementation may ameliorate this effect. Bisphosphonate treatment can improve both bone mineral density and vascular calcification, but the latter becomes more unlikely in patients with stage 3-4 CKD with vascular calcification but no decreased bone mineral density. Using bisphosphonates requires considerable caution in advanced CKD, and the lack of adequate clinical investigation necessitates more studies regarding its effects on these patients.
doi:10.1155/2013/837573
PMCID: PMC3899701  PMID: 24501586
21.  Management of Minerals and Bone Disorders after Kidney Transplantation 
Purpose of review
Mineral and bone disorders (MBD), inherent complications of moderate and advanced chronic kidney disease (CKD), occur frequently in kidney transplant recipients. However, much confusion exists about clinical application of diagnostic tools and preventive or treatment strategies to correct bone loss or mineral disarrays in transplanted patients. We have reviewed the recent evidence about prevalence and consequences of MBD in kidney transplant recipients and examined diagnostic, preventive and therapeutic options to this end.
Recent findings
Low turnover bone disease occurs more frequently after kidney transplantation according to bone biopsy studies. The risk of fracture is high, especially in the first several months after kidney transplantation. Alterations in minerals (calcium, phosphorus and magnesium) and biomarkers of bone metabolism (PTH, alkaline phosphatase, vitamin D and FGF-23) are observed with varying impact on post-transplant outcomes. Calcineurin inhibitors are linked to osteoporosis, whereas steroid therapy may lead to both osteoporosis and varying degrees of osteonecrosis. Sirolimus and everolimus might have a bearing on osteoblasts proliferation and differentiation or decreasing osteoclast mediated bone resorption. Selected pharmacologic interventions for treatment of MBD in transplant patients include steroid withdrawal, the use of bisphosphonates, vitamin D derivatives, calcimimetics, teriparatide, calcitonin and denosumab.
Summary
MBD following kidney transplantation is common and characterized by loss of bone volume and mineralization abnormalities often leading to low turnover bone disease. Although there are no well-established therapeutic approaches for management of MBD in renal transplant recipients, clinicians should continue individualizing therapy as needed.
doi:10.1097/MNH.0b013e3283546ee0
PMCID: PMC3532932  PMID: 22614626
Renal osteodystrophy; bisphosphonates; fracture; calcineurin inhibitor; adynamic bone
22.  Calcium Regulation and Bone Mineral Metabolism in Elderly Patients with Chronic Kidney Disease 
Nutrients  2013;5(6):1913-1936.
The elderly chronic kidney disease (CKD) population is growing. Both aging and CKD can disrupt calcium (Ca2+) homeostasis and cause alterations of multiple Ca2+-regulatory mechanisms, including parathyroid hormone, vitamin D, fibroblast growth factor-23/Klotho, calcium-sensing receptor and Ca2+-phosphate product. These alterations can be deleterious to bone mineral metabolism and soft tissue health, leading to metabolic bone disease and vascular calcification and aging, termed CKD-mineral and bone disorder (MBD). CKD-MBD is associated with morbid clinical outcomes, including fracture, cardiovascular events and all-cause mortality. In this paper, we comprehensively review Ca2+ regulation and bone mineral metabolism, with a special emphasis on elderly CKD patients. We also present the current treatment-guidelines and management options for CKD-MBD.
doi:10.3390/nu5061913
PMCID: PMC3725483  PMID: 23760058
calcium homeostasis; aging; chronic kidney disease; mineral and bone disorder; vascular calcification; secondary hyperparathyroidism
23.  A Structural Approach to Skeletal Fragility in Chronic Kidney Disease 
Seminars in nephrology  2009;29(2):133-143.
Renal osteodystrophy is a multifactorial disorder of bone metabolism in chronic kidney disease (CKD). As CKD progresses, ensuing abnormalities in mineral metabolism result in distortions in trabecular microarchitecture, thinning of the cortical shell, and increased cortical porosity. Recent studies have demonstrated significantly increased hip fracture rates in CKD stages 3 and 4, in dialysis patients, and in transplant recipients. The majority of studies of bone loss in CKD relied on dual energy x-ray absorptiometry (DXA) measures of bone mineral density (BMD). However, DXA summarizes the total bone mass within the projected bone area, concealing distinct structural alterations in trabecular and cortical bone. Recent data have confirmed that peripheral quantitative computed tomography (pQCT) measures of cortical density and thickness provide substantially better fracture discrimination in dialysis patients, compared with hip or spine DXA. The following review summarizes the growing evidence for bone fragility in CKD stages 3 through 5, considers the effects of CKD on trabecular and cortical bone structure as relates to fracture risk, and details the potential advantages and disadvantages of DXA and alternative measures of bone density, geometry, and microarchitecture, including pQCT, high resolution pQCT, and micro-magnetic resonance imaging for fracture risk assessment in CKD.
doi:10.1016/j.semnephrol.2009.01.006
PMCID: PMC2705768  PMID: 19371804
chronic kidney disease; renal osteodystrophy; fracture; DXA; bone mineral density
24.  TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I 
Pain  2007;137(3):507-519.
Tibia fracture in rats initiates a cascade of nociceptive, vascular, and bone changes resembling complex regional pain syndrome type I (CRPS I). Previous studies suggest that the pathogenesis of these changes is attributable to an exaggerated regional inflammatory response to injury. We postulated that the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) might mediate the development of CRPS-like changes after fracture. RT-PCR and EIA assays were used to evaluate changes in TNF expression and content in skin, nerve, and bone after fracture. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured using microcomputed tomography. Lumbar spinal cord Fos immunostaining was performed for quantification of Fos positive neurons. After baseline testing the distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were subcutaneously injected either with a soluble TNF receptor type 1 (sTNF-R1, 5mg/kg/d) or saline every 3 days over 28 days and then were retested at 4-weeks post-fracture. Tibia fracture chronically upregulated TNF expression and protein levels in the hindpaw skin and sciatic nerve. After fracture the rats developed hindpaw mechanical allodynia and unweighting, which were reversed by sTNF-R1 treatment. Consistent with the behavioral data, spinal Fos increased after fracture and this effect was inhibited by sTNF-R1 treatment. Collectively, these data suggest that facilitated TNF signaling in the hindlimb is an important mediator of chronic regional nociceptive sensitization after fracture, but does not contribute to the hindlimb warmth, edema, and bone loss observed in this CRPS I model.
doi:10.1016/j.pain.2007.10.013
PMCID: PMC2529181  PMID: 18035493
tibia fracture; neuropathic pain; TNF; sTNF-R1; microCT scanning; Fos immunoreactivity; complex regional pain syndrome
25.  Mineral and Bone Disease in Black African Hemodialysis Patients: A Report From Senegal 
Nephro-urology monthly  2012;4(4):613-616.
Background
Chronic kidney disease related mineral and bone disease (CKD-MBD) is a worldwide challenge in hemodialysis patients. In Senegal, number of dialysis patients is growing but few data are available about their bone disorders.
Objectives
To describe patterns of CKD-MBD in Senegalese dialysis patients.
Patients and Methods
We performed a cross-sectional study including patients from three dialysis centres in Senegal. Diagnosis of different types of CKD-MBD relied on clinical, biological and radiological data collected from medical records in dialysis.
Results
We included 118 patients and 79 of them presented CKD-BMD (prevalence of was 66.9 %). Mean age of CKD-MBD patients was 47.8 ± 15.7 years (16-81 years) and sex-ratio (Male/Female) was 1.15. Secondary hyperparathyroidism was the most frequent disorder (57 patients) followed by adynamic bone disease (21 patients) and osteomalacia (1 patients). The main clinical manifestations were bone pain (17.5% of cases), pruritus (36.8% of cases) and pathological fractures (2.5% of cases). Bone biopsy was not available. Valvular and peripheral vascular calcification were present in 24.5% and 21.2% of patients respectively. Management of CKD-MBD included optimization of dialysis, calcium bicarbonate, sevelamer, vitamin D analogues and calcimimetics. The NKF/DOQI recommended levels of serum calcium, phosphate and parathormone PTH were not achieved in one third of patients. Six patients presented major cardiovascular events during their dialysis period.
Conclusions
CKD-MBD are frequent in Senegalese hemodialysis patients and they are dominated by high turn-over disease. Clinical and biological manifestations are unspecific and accurate diagnoses are often difficult in absence of histomorphometry. Treatment is suboptimal for many patients in a context of limited resources.
doi:10.5812/numonthly.4225
PMCID: PMC3614308  PMID: 23573501
Renal Osteodystrophy; Hemodialysis; Senegal

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