Mary B. Leonard

Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease

Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.

Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.

CONTEXT A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. OBJECTIVE To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. MAIN OUTCOME MEASURES All-cause mortality and end-stage renal disease. RESULTS At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). CONCLUSION Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.

Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Pediatric Position Development Conference.

The International Society for Clinical Densitometry (ISCD) convenes a Position Development Conference (PDC) every 2 yr to make recommendations for standards in the field of bone densitometry. The recommendations are based on clinically relevant issues in bone densitometry such as quality control, acquisition, analysis, interpretation, and reporting. In 2007, ISCD convened its first Pediatric Position Development Conference to address issues specific to the assessment of skeletal health in children and adolescents. Topics for consideration are developed by the ISCD Board of Directors and its Scientific Advisory Committee. Clinically relevant questions related to each topic area are assigned to task forces for a comprehensive review of the medical literature and subsequent presentation of the reports to an international panel of experts. For this PDC, the Expert Panel included representatives of the American Society for Bone and Mineral Research and International Bone and Mineral Society. The recommendations of the PDC Expert Panel are then reviewed by the ISCD Board of Directors. Recommendations that are approved become Official Positions of the ISCD. The Pediatric PDC was held June 20-21, 2007, in Montreal, Quebec, Canada. Topics considered were restricted to children and adolescents, and included DXA prediction of fracture and definition of osteoporosis; DXA assessment in diseases that may affect the skeleton; DXA interpretation and reporting; and peripheral quantitative computed tomography measurement. This report describes the methodology and results of the 2007 Pediatric PDC, and a summary of all ISCD Official Positions, including the ones recently adopted by this 2007 Pediatric PDC and the 2007 Lansdowne, Virginia, USA Adult PDC.

International Society for Clinical Densitometry 2007 Adult and Pediatric Official Positions

The International Society for Clinical Densitometry (ISCD) periodically convenes Position Development Conferences (PDCs) in order to establish standards and guidelines for the assessment of skeletal health. The most recent Adult PDC was held July 20-22, 2007, in Lansdowne, Virginia, USA; the first Pediatric PDC was June 20-21, 2007 in Montreal, Quebec, Canada. PDC topics were selected according to clinical relevancy, perceived need for standardization, and likelihood of achieving agreement. Each topic area was assigned to a task force for a comprehensive review of the scientific literature. The findings of the review and recommendations were presented to adult and pediatric international panels of experts. The panels voted on the appropriateness, necessity, quality of the evidence, strength, and applicability (worldwide or variable according to local requirements) of each recommendation. Those recommendations that were approved by the ISCD Board of Directors become Official Positions. This is a review of the methodology of the PDCs and selected ISCD Official Positions.

Height Adjustment in Assessing Dual Energy X- Ray Absorptiometry Measurements of Bone Mass and Density in Children

CONTEXT In children, bone mineral content (BMC) and bone mineral density (BMD) measurements by dual-energy x-ray absorptiometry (DXA) are affected by height status. No consensus exists on how to adjust BMC or BMD (BMC/BMD) measurements for short or tall stature. OBJECTIVE The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children. DESIGN Data from the Bone Mineral Density in Childhood Study (BMDCS) were used to develop adjustment methods that were validated using an independent cross-sectional sample of healthy children from the Reference Data Project (RDP). SETTING We conducted the study in five clinical centers in the United States. PARTICIPANTS We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female). INTERVENTION No interventions were used. MAIN OUTCOME MEASURES We measured spine and whole body (WB) BMC and BMD Z-scores for age (BMC/BMD(age)), height age (BMC/BMD(height age)), height (BMC(height)), bone mineral apparent density (BMAD(age)), and height-for-age Z-score (HAZ) (BMC/BMD(haz)). RESULTS Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P < 0.005; r = 0.11 to 0.64) associated with HAZ. Spine BMD(haz) and BMC(haz)Z were not associated with HAZ; WB BMC(haz)Z was modestly associated with HAZ (r = 0.14; P = 0.0003). All other adjustment methods were negatively associated with HAZ (P < 0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P < 0.005) except for BMC/BMD(haz). CONCLUSIONS Most methods to adjust BMC/BMD Z-scores for height were biased by age and/or HAZ. Adjustments using HAZ were least biased relative to HAZ and age and can be used to evaluate the effect of short or tall stature on BMC/BMD Z-scores.

Chronic kidney disease and bone fracture: a growing concern.

Susceptibility to fracture is increased across the spectrum of chronic kidney disease (CKD). Moreover, fracture in patients with end-stage kidney disease (ESKD) results in significant excess mortality. The incidence and prevalence of CKD and ESKD are predicted to increase markedly over the coming decades in conjunction with the aging of the population. Given the high prevalence of both osteoporosis and CKD in older adults, it is of the utmost public health relevance to be able to assess fracture risk in this population. Dual-energy X-ray absorptiometry (DXA), which provides an areal measurement of bone mineral density (aBMD), is the clinical standard to predict fracture in individuals with postmenopausal or age-related osteoporosis. Unfortunately, DXA does not discriminate fracture status in patients with ESKD. This may be, in part, because excess parathyroid hormone (PTH) secretion may accompany declining kidney function. Chronic exposure to high PTH levels preferentially causes cortical bone loss, which may be partially offset by periosteal expansion. DXA can neither reliably detect changes in bone volume nor distinguish between trabecular and cortical bone. In addition, DXA measurements may be low, normal, or high in each of the major forms of renal osteodystrophy (ROD). Moreover, postmenopausal or age-related osteoporosis may also affect patients with CKD and ESKD. Currently, transiliac crest bone biopsy is the gold standard to diagnose ROD and osteoporosis in patients with significant kidney dysfunction. However, bone biopsy is an invasive procedure that requires time-consuming analyses. Therefore, there is great interest in developing non-invasive high-resolution imaging techniques that can improve fracture risk prediction for patients with CKD. In this paper, we review studies of fracture risk in the setting of ESKD and CKD, the pathophysiology of increased fracture risk in patients with kidney dysfunction, the utility of various imaging modalities in predicting fracture across the spectrum of CKD, and studies evaluating the use of bisphosphonates in patients with CKD.

KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD–Mineral and Bone Disorder (CKD-MBD)

This commentary provides a US perspective on the 2009 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). KDIGO is an independent international organization with the primary mission of the promotion, coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines for the care of patients with kidney disease. The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI), recognizing that international guidelines need to be adapted for each country, convened a group of experts to comment on the application and implementation of the KDIGO guideline for patients with CKD in the United States. This commentary puts the KDIGO guideline into the context of the supporting evidence and the setting of care delivered in the United States and summarizes important differences between prior KDOQI guidelines and the newer KDIGO guideline. It also considers the potential impact of a new bundled payment system for dialysis clinics. The KDIGO guideline addresses the evaluation and treatment of abnormalities of CKD-MBD in adults and children with CKD stages 3-5 on long-term dialysis therapy or with a kidney transplant. Tests considered are those that relate to laboratory, bone, and cardiovascular abnormality detection and monitoring. Treatments considered are interventions to treat hyperphosphatemia, hyperparathyroidism, and bone disease in patients with CKD stages 3-5D and 1-5T. Limitations of the evidence are discussed. The lack of definitive clinical outcome trials explains why most recommendations are not of level 1 but of level 2 strength, which means weak or discretionary recommendations. Suggestions for future research highlight priority areas.

Discrepancies in pediatric bone mineral density reference data: Potential for misdiagnosis of osteopenia

OBJECTIVE To evaluate published pediatric dual-energy x-ray absorptiometry bone mineral density (BMD) reference data by comparing the diagnostic classification of measured BMD in children at risk for osteopenia as healthy or osteopenic according to reference source. STUDY DESIGN Spine BMD was measured in 95 children, ages 9 to 15 years, at risk for osteopenia because of childhood disease. The BMD results were converted to age-specific z scores for each of the 5 reference data sets, and the z -score distributions were compared. RESULTS Between 11% and 30% of children were classified as osteopenic (z score < -2.0) depending on the reference data set. The 2 sex-specific reference data sets yielded similar diagnostic classification of boys and girls: 10% of boys and 11% to 16% of girls were osteopenic (P =.4). The 3 sex-nonspecific reference data sets classified 9% to 13% of girls and 24% to 44% of boys as osteopenic; the diagnosis of osteopenia was significantly greater in boys (P <.01). CONCLUSIONS The use of different published reference data for the assessment of children at risk for osteopenia results in inconsistent diagnostic classification of BMD results. These inconsistencies can be partially attributed to sex-nonspecific reference data that result in misclassification of boys as osteopenic.

Cortical Bone Water: In Vivo Quantification with Ultrashort Echo-Time MR Imaging

PURPOSE To develop and evaluate a method based on ultrashort echo-time radial magnetic resonance (MR) imaging to quantify bone water (BW) concentration as a new metric of bone quality in human cortical bone in vivo. MATERIALS AND METHODS Human subject studies were institutional review board approved and HIPAA compliant; informed consent was obtained. Cortical BW concentration was determined with custom-designed MR imaging sequences at 3.0 T and was validated in sheep and human cortical bone by using exchange of native water with deuterium oxide (D(2)O). The submillisecond T2* of BW requires correction for relaxation losses during the radiofrequency pulse. BW was measured at the tibial midshaft in healthy pre- and postmenopausal women (mean age, 34.6 and 69.4 years, respectively; n = 5 in each group) and in patients receiving maintenance hemodialysis (mean age, 51.8 years; n = 6) and was compared with bone mineral density (BMD) at the same site at peripheral quantitative computed tomography, as well as with BMD of the lumbar spine and hip at dual x-ray absorptiometry. Data were analyzed by using the Pearson correlation coefficient and two-sided t tests as appropriate. RESULTS Excellent agreement was obtained ex vivo between the water displaced by using D(2)O exchange and water measured with respect to a reference sample (r(2) = 0.99, P < .001). In vivo, BW in the postmenopausal group was greater by 65% (28.7% +/- 1.3 [standard deviation] vs 17.4% +/- 2.2, P < .001) than in the premenopausal group, and patients with renal osteodystrophy had higher BW (41.4% +/- 9.6) than the premenopausal group by 135% (P < .001) and the postmenopausal group by 43% (P = .02). BMD showed an opposite behavior, with much smaller group differences. Because the majority of BW is in the pore system of cortical bone, this parameter provides a surrogate measure for cortical porosity. CONCLUSION A new MR imaging-based method for quantifying BW noninvasively has been demonstrated.

Longitudinal Assessment of Bone Density and Structure in an Incident Cohort of Children With Crohn's Disease

BACKGROUND & AIMS The impact of childhood Crohns disease (CD) on volumetric bone mineral density (vBMD), bone structure, and muscle mass have not been established. The objective of this longitudinal study was to assess musculoskeletal outcomes in an incident cohort of children with CD using peripheral quantitative computed tomography (pQCT). METHODS Tibia pQCT was performed in 78 CD subjects (ages, 5-18 years) at diagnosis and in 67 over the subsequent year. pQCT outcomes were converted to sex- and race-specific z scores based on reference data in over 650 controls. Multivariable linear regression models identified factors associated with changes in bone outcomes. RESULTS At diagnosis, CD subjects had significant deficits in trabecular vBMD (z score, -1.32+/-1.32; P< .001), cortical section modulus (a measure of bone geometry and strength) (z score, -0.44+/-1.11; P< .01), and muscle (z score, -0.96+/-1.02; P< .001) compared with controls. Over the first 6 months, trabecular vBMD and muscle z scores improved significantly (both, P< .001); however, section modulus worsened (P= .0001), and all 3 parameters remained low after 1 year. Increases in muscle z scores were associated with less severe declines in cortical section modulus z scores. Improvements in trabecular vBMD z scores were greater in prepubertal subjects. Glucocorticoids were associated with increases in cortical vBMD. CONCLUSIONS Substantial deficits in trabecular vBMD, cortical bone geometry, and muscle were observed at CD diagnosis. Trabecular vBMD improved incompletely; however, cortical deficits progressed despite improvements in muscle. Glucocorticoids were not associated with bone loss. Therapies to improve bone accrual in childhood CD are needed.