Clinical Practice Guidelines

KDIGO Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention and Treatment of Chronic Kidney Disease related Mineral and Bone Disorders (CKD-MBD)

Disorders in mineral metabolism and bone disease are common complications of chronic kidney disease (CKD), and a significant cause of the morbidity and decreased quality of life of CKD patients. Importantly, there is an increasing body of convincing evidence suggesting that these disorders are associated with the increased risk for cardiovascular calcification, morbidity and mortality of these patients. The absence of a precise terminology and uniform classification of these abnormalities has hampered communication and comparison of reported research results, as well as the management of CKD patients afflicted by these disorders. In December of 2004, the Board of Directors of Kidney Disease: Improving Global Outcomes (KDIGO) selected addressing this gap as a priority action item.

As a first step in development of the guidelines, KDIGO convened in September of 2005 a Controversies Conference of international experts to develop consensus on a clear definition and improved classification scheme based on readily available clinical parameters that would enhance communication and direction of future research and form the basis of evidence-based clinical practice guidelines for the care of CKD patients.

The KDIGO position statement adopted as a result of the conference recommends that: (1) the term “renal osteodystrophy” be used exclusively to define alterations in bone morphology associated with CKD, which can be assessed by histology or more reliably by histomorphometry, and the results reported based on a unified classification system that includes parameters of Turnover, Mineralization and Volume (TMV system, Appendix, Table 1); and (2) the term CKD-Mineral and Bone Disorder (CKD-MBD) be used to describe the broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD, which is manifested by any one or a combination of the following: (1) Laboratory abnormalities of calcium, phosphorus, PTH or vitamin D metabolism; (2) Bone abnormalities in turnover, mineralization, volume, linear growth or strength; and (3) Calcification of the vasculature or other soft tissues, and classified based on the presence or absence of any combination of these three primary components (L,B,C, Appendix, Table 2).

The Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention and Treatment of CKD-MBD is the next step in this KDIGO priority action item that would allow for their translation into clinical practice. The major goal of these guidelines will be to:
(1) develop the evidentiary basis of the proposed recommendations; and (2) update the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease that were published in 2003 and frame them within the new definitions and classifications (Tables 1 and 2).

Issues to be addressed:

• The most sensitive and specific biochemical, bone and calcification tests for diagnosis of CKD-MBD
• The target levels for biochemical measures of CKD-MBD
• The prevalence of CKD-MBD at various stages of CKD
• The validity of the classification of CKD-MBD in predicating morbidity and mortality
• The most efficacious and safe treatment options for the various components of CKD-MBD

Topics to be considered:

CLASSIFICATION OF CKD-MBD:

• Definition and classification of CKD-MBD
• What proportion of patients at each stage of CKD has any form of CKD-MBD, and specific classes of CKD-MBD (L, LB, LC, LBC, Appendix, Table 2)? Does this differ in special populations such as diabetics, the elderly and children? Does this differ by nutritional status or geographical area?
• What is the predictive value does the proposed classification scheme of CKD-MBD have on morbidity and mortality?

EVALUATION CKD-MBD

A. Evaluation of biochemical markers:

• What serum levels of calcium, phosphorus, and PTH predict morbidity and
  mortality, bone abnormalities (histology, DEXA, qCT) and vascular calcification
  at each stage of CKD?
• What is the role of intact versus whole versus fragment versus ratio of PTH in predicting morbidity and mortality, bone abnormalities, and vascular calcification?
• What is the role of new biomarkers of bone turnover in predicting morbidity and mortality, bone abnormalities, and vascular calcification?
• What is the role of vitamin D (25(OH) D and 1,25 (OH)2 D) in predicting morbidity and mortality, bone abnormalities, and vascular calcification?

B. Evaluation of bone

• What predictive value does DEXA have for morbidity, mortality, bone histology and detection of fractures at each stage of CKD?
• What is the predictive value of other imaging modalities including plain radiographs, qCT and quantitative US for fractures, histology, and mortality
• What are the indications for bone biopsy?
• What are the most sensitive and specific measures for linear growth in pediatric patients?
• How do these measures of bone relate to measures of biochemical abnormalities and vascular calcification?

C. Evaluation of vascular calcification

• What is the sensitivity and specificity of various imaging techniques including plain radiograph, ultrasonography, electron-beam CT (EBCT), multiple slice CT (MSCT) for detecting vascular calcification of coronary arteries and aorta?
• What is the predictive value of such assessments for morbidity and mortality?
• How do non-invasive measures of vascular stiffening (pulse wave velocity, pulse pressure) correlate with the above imaging techniques for calcification?
• What is the correlation of these measures with biochemical markers and bone measures?
• How should vascular calcification be assessed in children?

TREATMENT OF CKD-MBD:

• Which therapy is best for the control of hyperphosphatemia?
• What are the major side effects of oral phosphate binders?
• What role do non-binder therapies play?
  Alternative dialysis regimens
  Calcimimetics

B. Treatment strategies for hyperparathyroidism

• Which therapy (oral calcium supplements, vitamin D oral vs. IV vs. type, calcimimetics, direct parathyroid injection of active vitamin D compounds, parathyroidectomy) is best for
• Lowering elevated PTH
• Avoiding over-suppressed PTH (and what is that?)
• Side effects

C. Treatment strategies for bone:

• What is the efficacy of standard anti osteoporotic therapies including bisphosphonates, calcitonin, estrogen, SERMs, and intermittent PTH on bone mineral density by DEXA, qCT and on bone fractures?
• What impact do therapies for control of serum phosphorus, calcium, and PTH have on bone as assessed by histology, DEXA, or qCT, on bone fractures and strength?

D. Treatment strategies for vascular calcification:

• What impact do therapies for control of serum phosphorus, calcium, and PTH have on vascular calcification?
• What impact do traditional therapies for atherosclerosis (i.e. statins) have on vascular calcification?

RESEARCH RECOMMENDATIONS

For each of the guidelines developed the Work Group will propose studies that are needed to provide necessary evidence where it is lacking or strengthen it where it is weak.

APPENDIX

Table 1. TMV Classification System for Renal Osteodystrophy

Table 2. A Framework for Classification of CKD-MBD

Legend: L= laboratory abnormalities; B = bone disease; C = calcification of vascular or other soft tissue.

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