Patients with chronic kidney disease (CKD) present with abnormalities in mineral and bone metabolism, which are associated with high morbidity and mortality. The most relevant bone abnormalities encompass suppressed or extremely elevated bone turnover and bone loss. Both turnover abnormalities and bone loss are associated with progressive calcifications, explaining the high morbidity and mortality. Bone biopsies are the gold standard for the diagnosis of bone abnormalities but are rarely performed. Noninvasive means to diagnose renal bone disease are urgently needed for implementation of targeted therapy to reduce morbidity and mortality. The long-term goal of the proposed study is to improve survival and quality of life in CKD patients by noninvasive detection of abnormalities in bone turnover and prevention of bone loss. This will allow administration of specific therapies and should contribute to reduction of disease burden and cost of a pervasive health problem affecting over 20 million patients in the United States. The central hypothesis is that renal osteodystrophy (ROD) can be defined noninvasively. Specifically, we will test the following hypotheses: 1. a) Bone volume component of ROD (bone loss) can be assessed by dual energy X-ray absorptiometry (DXA) and by quantitative computed tomography (QCT);however, QCT is more sensitive in recognizing bone loss;and, b) Bone loss occurs in patients with high and low turnover. Among patients with bone loss, there are at least 20% with low bone turnover. 2. The turnover component of ROD can be assessed noninvasively by PTH combined with established and/or novel biochemical markers of bone resorption and formation. The following specific aims will be pursued: 1. Comparison of DEXA and QCT for diagnosis of bone loss in CKD-5 patients and determination of the prevalence of low bone turnover in CKD-5 patients with bone loss. 2. Identification of the optimal combination of noninvasive tests for definition of the turnover component of ROD: For this purpose, 230 patients will be followed prospectively over 2 years, bone mass will be determined by QCT and DXA annually to establish the most sensitive means of identifying bone loss. Patients with osteoporosis at baseline and patients who develop bone loss at 1 or 2 years will be offered to undergo bone biopsy and blood drawing to measure serum markers of bone turnover, formation, and resorption. The best marker or combination of markers for definition of the turnover component ROD will be identified. Attainment of these goals will allow implementation of specific therapies without the use of invasive work-up and will assist in reducing morbidity, increasing survival, and improving quality of life in this unfortunate patient population.

Public Health Relevance

Cardiovascular and cerebrovascular calcifications are linked to abnormalities in bone turnover and bone loss resulting in high morbidity and mortality. Bone turnover abnormalities and bone loss occur in chronic kidney disease patients and bone biopsy (an invasive test) is considered essential for diagnosis of these bone abnormalities. The proposed studies will establish noninvasive means (a panel of blood tests and imaging methods) for recognition and characterization of these bone abnormalities which has significant implications, regarding diagnosis, prevention, treatment and a better understanding of the pathogenic mechanisms.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Kimmel, Paul
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University of Kentucky
Internal Medicine/Medicine
Schools of Medicine
United States
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Malluche, Hartmut H; Porter, Daniel S; Pienkowski, David (2013) Evaluating bone quality in patients with chronic kidney disease. Nat Rev Nephrol 9:671-80
Malluche, Hartmut H; Mawad, Hanna W; Monier-Faugere, Marie-Claude (2011) Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. J Bone Miner Res 26:1368-76
Cejka, Daniel; Herberth, Johann; Branscum, Adam J et al. (2011) Sclerostin and Dickkopf-1 in renal osteodystrophy. Clin J Am Soc Nephrol 6:877-82
Asci, Gulay; Ok, Ercan; Savas, Recep et al. (2011) The link between bone and coronary calcifications in CKD-5 patients on haemodialysis. Nephrol Dial Transplant 26:1010-5