Chronic kidney disease (CKD) prevalence is increasing rapidly and fracture incidence is much higher in patients with CKD than in the general population. Unfortunately, fracture risk prediction by dual energy X-ray absorptiometry (DXA) is poorer among CKD patients than in the general population and improved imaging methods are necessary to evaluate their fracture susceptibility. Ultra high resolution peripheral quantitative computed tomography (HRpQCT;resolution 80-100 um) is a novel technology that characterizes both cortical and trabecular microarchitecture. Finite element analysis (FEA), a measure of bone strength, can be applied to HRpQCT data sets. The hypotheses of this application are that CKD stages 3 to 5 are associated with progressive alterations in trabecular and cortical microarchitecture that reduce strength and increase fracture susceptibility, and HRpQCT with FEA, will provide greater fracture discrimination than DXA in patients with CKD. We will test this hypothesis in a cross-sectional study of 150 subjects with CKD stages 3 to 5 (75 with fracture). In a subset, we will validate HRpQCT measurements, established and novel markers of bone turnover against histomorphometry of transiliac bone biopsies. In CKD stage 4 subjects (n=50) we will longitudinally evaluate bone microarchitecure in relation to changes in kidney function. This study is highly relevant to public health, as fracture risk and its associated morbidity and mortality are exceedingly high in CKD patients and CKD and osteoporosis are highly coprevalent. This project also forms the training platform of my 5-year career development plan, the goal of which is to allow me to become an independent clinical investigator in the field of CKD-mineral and bone disorders (MBD). The plan includes didactic training in radiographic imaging, advanced biostatistics and epidemiological methods, specific hands-on training in HRpQCT, FEA and quantitative histomorphometry of transiliac bone biopsies with leading experts in the fields of bone biomechanics and bone cell biology, and frequent meetings with my mentor and co-mentor, leaders in the field of metabolic bone disease and CKD-MBD. During the award, I will develop expertise in using these tools to assess bone strength in CKD patients. In the fourth year, I will begin planning an RO1 submission. The skills and knowledge I acquire during this award will allow me to develop into a productive, independent investigator with a skill set that is unusual in the fields of nephrology and endocrinology.
This study is highly relevant to public health, as fracture risk and its associated morbidity and mortality are exceedingly high in CKD patients and CKD and osteoporosis are highly coprevalent.
|Jamal, S A; West, S L; Nickolas, T L (2014) The clinical utility of FRAX to discriminate fracture status in men and women with chronic kidney disease. Osteoporos Int 25:71-6|
|Babayev, Revekka; Nickolas, Thomas L (2014) Can one evaluate bone disease in chronic kidney disease without a biopsy? Curr Opin Nephrol Hypertens 23:431-7|
|Iyer, Sapna P; Nikkel, Lucas E; Nishiyama, Kyle K et al. (2014) Kidney transplantation with early corticosteroid withdrawal: paradoxical effects at the central and peripheral skeleton. J Am Soc Nephrol 25:1331-41|
|Nickolas, Thomas L; Stein, Emily M; Dworakowski, Elzbieta et al. (2013) Rapid cortical bone loss in patients with chronic kidney disease. J Bone Miner Res 28:1811-20|
|Nikkel, Lucas E; Iyer, Sapna P; Mohan, Sumit et al. (2013) Pancreas-kidney transplantation is associated with reduced fracture risk compared with kidney-alone transplantation in men with type 1 diabetes. Kidney Int 83:471-8|
|Nickolas, Thomas L; Forster, Catherine S; Sise, Meghan E et al. (2012) NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney disease. Kidney Int 82:718-22|
|Liu, X Sherry; Stein, Emily M; Zhou, Bin et al. (2012) Individual trabecula segmentation (ITS)-based morphological analyses and microfinite element analysis of HR-pQCT images discriminate postmenopausal fragility fractures independent of DXA measurements. J Bone Miner Res 27:263-72|
|Misof, Barbara M; Gamsjaeger, Sonja; Cohen, Adi et al. (2012) Bone material properties in premenopausal women with idiopathic osteoporosis. J Bone Miner Res 27:2551-61|
|Nikkel, L E; Mohan, S; Zhang, A et al. (2012) Reduced fracture risk with early corticosteroid withdrawal after kidney transplant. Am J Transplant 12:649-59|
|Nickolas, Thomas L; Schmidt-Ott, Kai M; Canetta, Pietro et al. (2012) Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study. J Am Coll Cardiol 59:246-55|
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