Highlights of the KDIGO Bone and Mineral Disorder Guidelines

During the 1980s and 1990s, the focus of dealing with disorders of bone and mineral metabolism was predominantly “bone centric,” with parathyroid hormone (PTH) the main culprit and calcium the primary regulator of PTH. The term “renal osteodystrophy” was generally used to encompass these disorders. The focus of therapy was to maintain relatively high serum calcium concentrations in order to suppress PTH, which would presumably result in normal bone. This strategy did result in decreased PTH concentrations with the use of relatively high dialysate calcium baths, calcium-based phosphate binders and calcitriol; however, this practice resulted in hypercalcemia. As a result, non-calcium–containing phosphate binders and less-calcemic vitamin D receptor activators (VDRAs) were developed. During this time, there was also an increased awareness of the importance of phosphate, and more recently a better understanding of the hormonal regulation of phosphate metabolism with the identification of phosphatonins, predominantly fibroblastic growth factor 23 (FGF23). In addition, a greater appreciation of the role of extraskeletal calcification, predominantly vascular, and the prevalence and severity of fractures in the CKD population became apparent.

In 2003, clinical practice guidelines for bone and mineral metabolism were published by the Kidney Disease Outcomes Quality Initiative (KDOQI). The guidelines were largely based on expert opinion rather than evidence, and were “phosphorus and PTH centric.” Since these guidelines were released significant progress has been made in understanding the roles of VDRAs, the calcimimetic agent cinacalcet, FGF23, and possibly alkaline phosphatase. It has become apparent that mineral disorders of CKD were not solely a problem of bone disease.

In 2006, KDOQI created a consensus group to better define the diseases associated with altered mineral metabolism in CKD, which they termed chronic kidney disease–mineral and bone disorder (CKD-MBD). It is a systemic disorder of mineral and bone metabolism found in patients with CKD manifested by either one or a combination of the following: Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism, Abnormalities in bone turnover, mineralization, volume, linear growth, or strength, and/or vascular or soft tissue calcification.
 

It is important to note that this list was not intended to be all encompassing and could expand as our understanding of disordered mineral metabolism evolves. The term renal osteodystrophy should now be limited to pathologic changes of bone morphology related to progressive CKD; and is quantifiable by histomorphometry based on bone biopsy (1). It is characterized by alterations in bone turnover, mineralization, and volume and includes the following qualitative disorders of bone: osteitis fibrosis cystica, adynamic bone disease, osteomalacia, and mixed uremic osteodystrophy (2).

In 2008, Kidney Disease: Improving Global Outcomes (KDIGO) presented a preliminary draft of the guidelines for CKD-MBD for public review. The KDIGO Work Group took a more conservative approach and refrained from making specific guidelines on treatment due to lack of high-quality evidence. This was a dramatic shift from the previous 2003 KDOQI guidelines, which had recommended specific targets for calcium, phosphorus, and PTH. Reviewers of the preliminary draft and the KDIGO board asked that the Work Group provide recommendations even if these were based largely on expert judgment, as long as the Work Group could achieve consensus.

Consequently, in 2009 KDIGO presented the final clinical practice guidelines for the management of CKD-MBD (3). The major difference between the KDOQI and KDIGO guidelines (Table 1) was that the KDIGO followed more stringent criteria for including studies to grade the evidence.

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KDIGO presented two levels of recommendations based on evidence. Level 1 is “we recommend,” and implies that most patients should receive the course of action. Level 2 is “we suggest,” and implies that the choices are likely debatable. Most of the guidelines (approximately 80 percent) were graded Level 2 due to the lack of evidence and/or good randomized controlled trials, and it was left up to the clinician to make a decision based on the clinical circumstances of the individual patient.

Unfortunately, the publication of these guidelines has resulted in more controversy rather than therapeutic guidance. A meta-analysis published in 2011 of 47 cohort studies concluded that the current guidelines for calcium, phosphorus, and PTH in CKD patients are poor. They were critical of the KDIGO guidelines in that it “promotes therapeutic strategies without sufficient evidence” and that “high-quality evidence is required before specific treatment should be advocated strongly” (4).

A commentary response to this meta-analysis by a member who was on the KDIGO Work Group does not dispute that there was insufficient data, but tries to address “what should a guideline panel do when evidence is inconclusive.” It reports that even when there is lack of evidence, most clinicians prefer to have at least an educated opinion from a guideline committee with a transparent rationale provided as a point of reference (5).

Key questions still need to be answered regarding target phosphate and PTH levels and an optimal treatment strategy for achieving phosphate and PTH targets. There is an urgent need for well conducted randomized control trials in the CKD and dialysis population to address these questions. However, in the interim, it seems reasonable to use the KDIGO recommendations as a guideline.

Notes

[1] Menaka Sarav, MD, and Stuart M. Sprague, DO, FACP, FASN, are affiliated with the Division of Nephrology and Hypertension at North Shore University Health System in Evanston, IL.

References

1. Moe S, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 69:1945–1953.

2. Sprague SM. Renal bone disease. Curr Opin Endocrinol Diabetes Obes 2010; 17:535–539.

3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009; 113:S1–S130.

4. Palmer SC, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA 2011; 305:1119–1127.

5. Uhlig K. What should a guideline panel do when evidence is inconclusive? The case of treatments for CKD-mineral and bone disorder (CKD-MBD). Am J Kidney Dis 2011; 58:872–875.

6. Uhlig K, et al. KDOQI US commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis 2010; 55:773–799.

7. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42 (4 Suppl 3):S1–S201.

April 2013 (Vol. 5, Number 4)​