Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)

Disturbances in mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and are an important cause of morbidity, decreased quality of life, and extraskeletal calcification that have been associated with increased cardiovascular mortality. These disturbances have traditionally been termed renal osteodystrophy and classified based on bone biopsy. Kidney Disease: Improving Global Outcomes (KDIGO) sponsored a Controversies Conference on Renal Osteodystrophy to (1) develop a clear, clinically relevant, and internationally acceptable definition and classification system, (2) develop a consensus for bone biopsy evaluation and classification, and (3) evaluate laboratory and imaging markers for the clinical assessment of patients with CKD. It is recommended that (1) the term renal osteodystrophy be used exclusively to define alterations in bone morphology associated with CKD, which can be further assessed by histomorphometry, and the results reported based on a unified classification system that includes parameters of turnover, mineralization, and volume, and (2) the term CKD-Mineral and Bone Disorder (CKD-MBD) be used to describe a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD, which is manifested by abnormalities in bone and mineral metabolism and/or extra-skeletal calcification. The international adoption of these recommendations will greatly enhance communication, facilitate clinical decision-making, and promote the evolution of evidence-based clinical practice guidelines worldwide. Disturbances in mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and are an important cause of morbidity, decreased quality of life, and extraskeletal calcification that have been associated with increased cardiovascular mortality. These disturbances have traditionally been termed renal osteodystrophy and classified based on bone biopsy. Kidney Disease: Improving Global Outcomes (KDIGO) sponsored a Controversies Conference on Renal Osteodystrophy to (1) develop a clear, clinically relevant, and internationally acceptable definition and classification system, (2) develop a consensus for bone biopsy evaluation and classification, and (3) evaluate laboratory and imaging markers for the clinical assessment of patients with CKD. It is recommended that (1) the term renal osteodystrophy be used exclusively to define alterations in bone morphology associated with CKD, which can be further assessed by histomorphometry, and the results reported based on a unified classification system that includes parameters of turnover, mineralization, and volume, and (2) the term CKD-Mineral and Bone Disorder (CKD-MBD) be used to describe a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD, which is manifested by abnormalities in bone and mineral metabolism and/or extra-skeletal calcification. The international adoption of these recommendations will greatly enhance communication, facilitate clinical decision-making, and promote the evolution of evidence-based clinical practice guidelines worldwide. Chronic kidney disease (CKD) is a worldwide public health problem, with increasing prevalence and adverse outcomes, including progressive loss of kidney function, cardiovascular disease, and premature death.1.Eknoyan G. Lameire N. Barsoum R. et al.The burden of kidney disease: improving global outcomes.Kidney Int. 2004; 66: 1310-1314Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar Disturbances in mineral metabolism and bone disease are common complications of CKD and an important cause of morbidity and decreased quality of life. Importantly, there is increasing evidence suggesting that these disorders in mineral and bone metabolism are associated with increased risk for cardiovascular calcification, morbidity, and mortality.2.Block G.A. Cunningham J. Morbidity and mortality associated with abnormalities in bone and mineral metabolism in CKD.in: Olgaard K. Clinical Guide to the Basics of Bone and Mineral Metabolism in CKD. National Kidney Foundation, New York2006: 77-92Google Scholar The underlying mechanisms for this linkage are not completely understood, but are probably related to an effect on vascular calcification (VC) leading to changes in cardiovascular structure and function.3.Ketteler M. Gross M.L. Ritz E. Calcification and cardiovascular problems in renal failure.Kidney Int. 2005; 94: S120-S127Abstract Full Text Full Text PDF Google Scholar, 4.London G.M. Marchais S.J. Guerin A.P. Metivier F. Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia.Curr Opin Nephrol Hypertens. 2005; 14: 525-531Crossref PubMed Scopus (207) Google Scholar Evaluation of extraskeletal calcification therefore becomes an essential component in the work up and classification of the mineral and bone disorders in patients with CKD. Renal osteodystrophy is the term that has been used traditionally to describe the abnormalities in bone morphology that develop in CKD.5.Coen G. Ballanti P. Bonucci E. et al.Renal osteodystrophy in predialysis and hemodialysis patients: comparison of histologic patterns and diagnostic predictivity of intact PTH.Nephron. 2002; 91: 103-111Crossref PubMed Scopus (90) Google Scholar, 6.Freemont T. Malluche H.H. Utilization of bone histomorphometry in renal osteodystrophy: demonstration of a new approach using data from a prospective study of lanthanum carbonate.Clin Nephrol. 2005; 63: 138-145Crossref PubMed Scopus (29) Google Scholar, 7.Ho L.T. Sprague S.M. Percutaneous bone biopsy in the diagnosis of renal osteodystrophy.Semin Nephrol. 2002; 22: 268-275Abstract Full Text PDF PubMed Scopus (10) Google Scholar, 8.Lehmann G. Stein G. Huller M. et al.Specific measurement of PTH (1-84) in various forms of renal osteodystrophy (ROD) as assessed by bone histomorphometry.Kidney Int. 2005; 68: 1206-1214Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar In clinical practice, bone biopsy is used infrequently because it is an invasive and often expensive procedure and the samples obtained require specialized processing that is not widely available. The most common forms of renal osteodystrophy are attributable largely to variations in the plasma levels of parathyroid hormone (PTH). As such, circulating PTH levels have been used as a surrogate indicator of bone turnover, which are used together with measurements of serum calcium, phosphorus, and alkaline phosphatase levels to evaluate, diagnose, and guide the treatment of renal osteodystrophy. However, the specificity of PTH as an indicator of bone turnover has been questioned.9.Goodman W.G. The evolution of assays for parathyroid hormone.Semin Dial. 2005; 18: 296-301Crossref PubMed Scopus (19) Google Scholar, 10.Martin K.J. Olgaard K. Coburn J.W. et al.Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodystrophy.Am J Kidney Dis. 2004; 43: 558-565Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Several other circulating biochemical markers of bone formation and resorption have been investigated as clinical indicators of bone turnover,11.Ferreira A. Drueke T.B. Biological markers in the diagnosis of the different forms of renal osteodystrophy.Am J Med Sci. 2000; 320: 85-89Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 12.Urena P. de Vernejoul M.C. Circulating biochemical markers of bone remodeling in uremic patients.Kidney Int. 1999; 55: 2141-2156Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar but their clinical applicability remains to be established. In addition to bone histology and serum biomarkers, imaging has been an important component of evaluating bone disease in the past, and remains the main tool in assessing extraskeletal calcification in CKD patients.13.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1433) Google Scholar Ongoing developments in non-invasive imaging techniques almost certainly will lead to their improved and more widespread use in clinical diagnosis and decision-making in the near future.14.Bellasi A. Raggi P. Diagnostic and prognostic value of coronary artery calcium screening.Curr Opin Cardiol. 2005; 20: 375-380Crossref PubMed Scopus (26) Google Scholar In principle, the definition, evaluation, and classification of the mineral abnormalities and bone disease in CKD should include all three clinical components: serum biomarkers, non-invasive imaging, and bone abnormalities. Unfortunately, to date, there is no clear definition of renal osteodystrophy that incorporates all these components of disorders in mineral and bone metabolism encountered in CKD. At the 2003 National Kidney Foundation Controversies Conference on Mineral Metabolism and Bone Disease in CKD, the following definition for renal osteodystrophy was proposed: A constellation of bone disorders present or exacerbated by chronic kidney disease that lead to bone fragility and fractures, abnormal mineral metabolism, and extraskeletal manifestations.15.Moe S.M. Drueke T.B. A bridge to improving healthcare outcomes and quality of life.Am J Kidney Dis. 2004; 43: 552-557Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar This definition, which incorporates the relevant elements of mineral and bone abnormalities and soft tissue calcification, has failed to gain worldwide acceptance. The historical absence of a generally accepted definition and diagnosis of renal osteodystrophy indicates the need for an international consensus, which the Board of Directors of Kidney Disease: Improving Global Outcomes (KDIGO) selected as a priority issue to address. KDIGO was established in 2003 as an independently incorporated non-profit foundation governed by an international board of directors with the stated mission to ‘improve the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration and integration of initiatives to develop and implement clinical practice guidelines’. One of the initiatives adopted by the KDIGO Board of Directors is a series of international Controversies Conferences to examine what is known, what can be done with what is known, and what needs to be known on controversial topics of clinical relevance. The first KDIGO Controversies Conference on ‘Definition and Classification of Chronic Kidney Disease’ was held in 2004.16.Levey A.S. Eckardt K.U. Tsukamoto Y. et al.Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2005; 67: 2089-2100Abstract Full Text Full Text PDF PubMed Scopus (2202) Google Scholar The second KDIGO Controversies Conference on ‘Definition, Evaluation, and Classification of Renal Osteodystrophy’ was held on September 15–17, 2005 in Madrid, Spain. The specific objectives for this conference were todevelop a clinically relevant, easily applicable definition and classification system for the constellation of disorders heretofore known as renal osteodystrophy;examine current histologic categories of renal osteodystrophy and develop consensus on a unified evaluation and classification of bone histology; andevaluate and assess the clinical utility of serum markers and imaging procedures that can allow the non-invasive diagnosis and classification of mineral and bone disorders specifically associated with CKD with reasonable accuracy. The adoption of a clear definition and improved classification scheme based on readily available clinical parameters would greatly enhance the direction of future research and the development and implementation of evidence-based clinical practice guidelines for the management of mineral and bone abnormalities in CKD. KDIGO co-chairs (G Eknoyan and N Lameire) identified the conference co-chairs (T Drüeke and S Moe) and worked together to develop the agenda and participants list. Meeting participants were chosen based on their demonstrated expertise in mineral and bone metabolism and interest in global issues in guideline development and implementation. The conference was attended by more than 70 physicians, representing six continents and 21 countries (see Appendix A1). Prior to the conference, each of the participants was invited to submit an abstract of their work and concerns to facilitate the meeting discussions. Those abstracts and the conference agenda can be found at www.kdigo.org. The meeting started with a plenary session during which a series of presentations were made, designed to provide both a historical perspective and an overview of recent developments in the areas of bone biopsy and histomorphometry, serum markers of bone metabolism, and assessment of bone health with imaging techniques. The plenary session was followed by breakout sessions of three separate work groups to address the following topics: bone biopsy and histomorphometry, biomarkers, and imaging techniques. Each of the work groups was asked to make recommendations on a name, definition, and classification system for the disorder. They were also challenged to critically examine the diagnostic parameters specific to their topic area and make recommendations on their utility and validity in the evaluation of the disease, and to make recommendations to guide clinical research studies aimed at evaluating the adequacy of their proposals. Owing to the complexity of the meeting objectives for the bone biopsy work group, members of this group were invited to begin their deliberations a day earlier than those of the other two work groups. On the final day, work group leaders presented a summary of their group's deliberations and recommendations to the entire conference assembly. After discussion and refinement of the recommendations, the conference participants prioritized and voted on the recommendations. This paper contains the specific recommendations made at the meeting. It has been reviewed by the participants and approved as a position statement by the KDIGO Board of Directors. There was general agreement among the conference attendees on the following issues:The traditional definition of renal osteodystrophy does not completely depict the underlying bone pathology or reflect the full spectrum of symptoms associated with mineral and bone disorders in CKD.Bone biopsy remains a powerful and informative diagnostic tool for the determination of bone abnormalities. However, owing to its limited use, a biopsy-based definition and classification system does not provide an adequate means in clinical practice to clearly identify and classify CKD patients with mineral and bone disorders.Although the mechanisms involved are still poorly understood, there is a clear association in CKD patients between mineral and bone abnormalities and the incidence and severity of VC and cardiovascular morbidity and mortality. The presence of abnormal values of circulating markers such as plasma phosphorus, as well as the presence and extent of VC, is associated with increased cardiovascular and all-cause morbidity and mortality in CKD stage 5 patients on hemodialysis.17.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1181) Google Scholar Minimizing abnormalities in biochemical markers, such as hyperphosphatemia and hypercalcemia, and slowing or halting the progression of extraskeletal calcification is considered a critical component of the management of CKD patients for the prevention of bone disease and other related morbidities and mortality.18.Asmus H.G. Braun J. Krause R. et al.Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density.Nephrol Dial Transplant. 2005; 20: 1653-1661Crossref PubMed Scopus (150) Google Scholar, 19.Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1269) Google Scholar, 20.Moe S.M. Uremic vasculopathy.Semin Nephrol. 2004; 24: 413-416Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar The principal conclusion from the conference was that the current descriptive nomenclature for this pathophysiologic process should be reconsidered. It is recommended that the term renal osteodystrophy be used exclusively to define the bone pathology associated with CKD. The many clinical, biochemical, and imaging abnormalities that have heretofore been identified as correlates of renal osteodystrophy should be defined more broadly as a clinical entity or syndrome to be called chronic kidney disease-mineral and bone disorder (CKD-MBD). Conference participants examined these two issues separately and made recommendations for the definition, evaluation, and classification of each. The meeting participants agreed on a definition of renal osteodystrophy that is specific to bone pathology found in patients with CKD (Table 1). Renal osteodystrophy is one component of the mineral and bone disorders that occur as a complication of CKD. CKD, chronic kidney disease; CKD-MBD, chronic kidney disease-mineral and bone disorder. The evaluation and definitive diagnosis of renal osteodystrophy requires a bone biopsy. Histomorphometry is not essential for clinical diagnosis, but should be performed in research studies. There was unanimous agreement that histomorphometric results are to be reported using standard nomenclature as recommended by the American Society for Bone and Mineral Research,21.Parfitt A.M. Drezner M.K. Glorieux F.H. et al.Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee.J Bone Miner Res. 1987; 2: 595-610Crossref PubMed Scopus (4770) Google Scholar and that investigators would supply primary measurements used to report any derived parameters. In order to clarify the interpretation of bone biopsy results in the evaluation of renal osteodystrophy, it was agreed to use three key histologic descriptors – bone turnover, mineralization, and volume (TMV system) – with any combination of each of the descriptors possible in a given specimen (Table 2). The TMV classification scheme provides a clinically relevant description of the underlying bone pathology as assessed by histomorphometry, which in turn helps define the pathophysiology, and thereby guide therapy. TMV, bone turnover, mineralization, and volume. The meeting participants agreed on a definition of CKD-MBD (Table 3) that incorporates elements of abnormal mineral metabolism, altered bone structure and composition, and extraskeletal calcification with the following caveats:Bone disease and VC are discreet entities that are not exclusive to the CKD population.Bone disease and VC are multifactorial processes, and disturbances in mineral metabolism due to CKD may not be their primary underlying etiology.The evidence for a link between mineral disturbances and VC in CKD is not yet fully established. CKD, chronic kidney disease; CKD-MBD, chronic kidney disease-mineral and bone disorder; PTH, parathyroid hormone. The initial evaluation of CKD-MBD should include PTH, calcium (either ionized or total corrected for albumin), phosphorus, alkaline phosphatases (total or bone-specific), bicarbonate, and imaging for soft tissue calcification.If there are inconsistencies in the biochemical markers (e.g. high PTH but low alkaline phosphatases), unexplained bone pain, or unexplained fractures, a bone biopsy would be indicated.Additional tests to assess linear growth rate are needed in children with CKD. Disease classification systems can be simple or complex and may be based on severity, prognosis, outcomes, symptoms, or treatment modalities. General considerations in the adoption of a classification system include (1) availability of supporting data, (2) ease of clinical use, and (3) appropriateness in guiding clinical therapy. An ideal classification system for CKD-MBD would allow categorization of patients based on readily available clinical diagnostic tools and would help guide treatment. The lack of adequate data and the nonlinearity of the disease process do not allow for the development of a classification based on severity or treatment at this time. The proposed framework for classifying CKD-MBD (Table 4) divides patients into four types based on the presence or absence of abnormalities in the three primary components used in the definition of the disorder: laboratory abnormalities (L), bone disease (B), and calcification of extraskeletal tissue (C). This framework is meant to be descriptive rather than predictive, as an initial attempt to improve communication and stimulate research. It is a working model that may have to be modified and improved in the future depending on further analysis of new data that become available. This simple framework lends itself to subsequent critical evaluation and refinement based on analysis of patient databases or the prospective evaluation of CKD patients. CKD-MBD, chronic kidney disease-mineral and bone disorder; PTH, parathyroid hormone. The use of CKD-MBD should be as specific as possible and limited to disturbances caused by significantly reduced kidney function. In general, adult patients with a glomerular filtration rate of >60 ml/min/1.73 m2 should be excluded, as this is the level of glomerular filtration rate below which abnormalities in calcium, phosphorus, PTH, and vitamin D metabolism are detectable. In pediatric patients, the level of glomerular filtration rate at which CKD-MBD abnormalities are detectable is higher (glomerular filtration rate <89 ml/min/1.73 m2). On the other hand, increased bone fragility observed with aging (senile or post-menopausal osteoporosis) and atherosclerotic disease with calcification that develops independent of CKD can be present in patients with CKD who have normal or only slightly reduced kidney function, and can coexist with CKD-MBD after its onset. This is an important consideration, as CKD may alter the diagnosis, treatment, and prognosis of osteoporosis and atherosclerosis. Bone, in particular, is likely to be more severely affected by CKD than might be expected from normal aging, either because of the extremes of turnover or remodeling that occur in CKD in adults and children, or because of abnormalities of modeling that occur in growing children. This in turn might have a major impact on bone strength, perhaps even more so than that of altered bone mass or volume. Because of this, the term osteoporosis should not be used in describing altered bone fragility in CKD patients.22.Cunningham J. Sprague S.M. Cannata-Andia J. et al.Osteoporosis in chronic kidney disease.Am J Kidney Dis. 2004; 43: 566-571Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar By the same token, several studies have demonstrated that for any age group the atherosclerotic lesions are more calcified in CKD patients than in the general population.23.Schwarz U. Buzello M. Ritz E. et al.Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure.Nephrol Dial Transplant. 2000; 15: 218-223Crossref PubMed Scopus (509) Google Scholar The presence of increased calcification in these cases may affect the response to common therapies such as angioplasty. Thus, although CKD-MBD should refer to conditions that are caused by CKD, the precise contribution of CKD-related changes to disease states commonly found in the general population will require increased understanding of the underlying pathophysiology, more sensitive diagnostic tools, and a different therapeutic approach. 1. Indications for bone biopsy: Bone biopsy is not recommended as part of the routine evaluation for CKD-MBD, but remains a valuable diagnostic tool in the clinical evaluation and differential diagnosis of bone disease in selected patients with CKD. The clinical indications for bone biopsy include, but are not limited to the following:inconsistencies among biochemical parameters that preclude a definitive interpretation,unexplained skeletal fracture or bone pain,severe progressive VC,unexplained hypercalcemia,suspicion of overload or toxicity from aluminum, and possibly other metals,before parathyroidectomy if there has been significant exposure to aluminum in the past or if the results of biochemical determinations are not consistent with advanced secondary or tertiary hyperparathyroidism, andto be considered before beginning treatment with bisphosphonates. 2. Histologic classification based upon TMV (turnover/mineralization/volume): A standardized nomenclature for reporting the results of bone histomorphometry, both for clinical and for research purposes, has been provided by the American Society for Bone and Mineral Research (ASBMR).21.Parfitt A.M. Drezner M.K. Glorieux F.H. et al.Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee.J Bone Miner Res. 1987; 2: 595-610Crossref PubMed Scopus (4770) Google Scholar It is recommended that the same nomenclature be utilized for the assessment of renal osteodystrophy to promote a more widespread and consistent understanding of bone histomorphometry and the information that it provides. Such an approach would also facilitate valid comparisons among results from various research reports. If calculated parameters are used, it is expected that the primary measurements used to derive them are made available, using appendices or internet databases as necessary. The components used to classify renal osteodystrophy include turnover, mineralization, and bone volume using the TMV classification system (Table 2). This new classification is consistent with the current commonly used one,24.Sherrard D.J. Hercz G. Pei Y. et al.The spectrum of bone disease in end-stage renal failure – an evolving disorder.Kidney Int. 1993; 43: 436-442Abstract Full Text PDF PubMed Scopus (637) Google Scholar but provides more information on parameters other than turnover (Figure 1).Turnover reflects the rate of skeletal remodeling, which is normally the coupled process of bone resorption and bone formation. It is assessed with histomorphometry by dynamic measurements of osteoblast function using the technique of double-tetracycline labeling. Bone formation rates and activation frequency represent acceptable parameters for assessing bone turnover. When bone formation rate is reported, the referent (bone surface, area, volume or tissue volume) should be specified. If expressed as a categorical variable (low, normal, or high), the cutoff values should be included. Bone turnover is affected mainly by hormones, cytokines, mechanical stimuli, and growth factors that influence the recruitment, differentiation, and activity of osteoclasts and osteoblasts. It is important to clarify that although bone formation rate is frequently similar to bone resorption rate, which cannot be measured directly, this is not always true. Imbalance in these processes can affect bone volume. For example, excess resorption over formation will lead to negative bone balance and decreased bone volume.Mineralization reflects how well bone collagen becomes calcified during the formation phase of skeletal remodeling. It is assessed with histomorphometry by static measurements of osteoid volume and osteoid thickness and by dynamic, tetracycline-based measurements of mineralization lag time and osteoid maturation time. Causes of impaired mineralization include inadequate vitamin D nutrition, mineral deficiency, acidosis, or bone aluminum toxicity.Volume indicates the amount of bone per unit volume of tissue. It is assessed with histomorphometry by static measurements of bone volume in cancellous bone. Sometimes, measurements of cortical bone volume and thickness may provide additional useful information. Determinants of bone volume in the general population and CKD patients include age, gender, race, genetic factors, nutrition, endocrine disorders, mechanical stimuli, toxicities, neurological function, vascular supply, growth factors, and cytokines. 3. Reporting of results: It is recommended that publications that report histomorphometric measurements should include the following details in the methods section: biopsy technique, specimen size, tetracycline protocol, assessment of sample adequacy (e.g. exclusions due to crush artifacts), tissue area that was measured, magnification, minimal osteoid width measured, and normative data source when appropriate. Each reporting laboratory should perform assessment studies of their methodology precision. 4. Quality assurance: There is a clear need to establish a cooperative international initiative to facilitate the development of a global quality assurance program and a data collection mechanism for bone histomorphometry results in CKD. Objectives include the following:Develop a quality control and assurance protocol with ongoing inter-laboratory exchange of bone biopsy material to determine the variability of histomorphometric results among laboratories and to promote standardization for the reporting of results.Develop a mechanism to collect all currently available normative data for bone biopsies, including an international effort to prospectively obtain bone biopsy samples from healthy volunteers. This should include evaluation of age, gender, and race variations in different geographic regions. What changes in bone histomorphometry parameters occur as CKD progresses from stage 2 to 5?What is the relationship of bone histomorphometric abnormalities to vascular and other s