Canadian Society of Nephrology Commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD–Mineral and Bone Disorder (CKD-MBD)

Article Outline

• Introduction
• Review and Approval Process for CSN Guidelines and Commentaries
• Structure of This Commentary
• Review of KDIGO Recommendations
  • Diagnosis of CKD-MBD: Biochemical Abnormalities
    • Commentary on Chapter 3.1
    • Implications Within Canadian Health Care
  • Diagnosis of CKD-MBD: Bone
    • Commentary on Chapter 3.2
    • Implications Within Canadian Health Care
  • Diagnosis of CKD-MBD: Vascular Calcification
    • Commentary on Chapter 3.3
    • Implications Within Canadian Health Care
  • Treatment of CKD-MBD Targeted at Lowering High Serum Phosphorus and Maintaining Serum Calcium
    • Commentary on Chapter 4.1
    • Implications Within Canadian Health Care
  • Treatment of Abnormal PTH Levels in CKD–MBD
    • Commentary on Chapter 4.2
    • Implications Within Canadian Health Care
  • Treatment of Bone With Bisphosphonates, Other Osteoporosis Medications, and Growth Hormone
    • Commentary on Chapter 4.3
    • Implications Within Canadian Health Care
• Conclusion
• Acknowledgements
• Appendix
• References
• Copyright

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Introduction 

Professional societies throughout the world, including the Canadian Society of Nephrology (CSN), agree there is a need for developing clinical practice guidelines for patients with chronic kidney disease (CKD). However, as illustrated by the case of the plethora of anemia guidelines for CKD that have been completed (and updated) by many national professional societies since 2000,¹, ², ³, ⁴, ⁵ creation of guidelines by individual professional societies results in significant duplication of effort. In this context, KDIGO (Kidney Disease: Improving Global Outcomes) was established in 2003 with its 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.”⁶

The KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) represents a 2-year comprehensive effort to review the relevant evidence in CKD-MBD.⁶ The CSN congratulates KDIGO on an excellent review of the available evidence.

Although the CSN welcomes the KDIGO evidence synthesis and global clinical practice guidelines initiative, the CSN¹ and other professional societies, including Kidney Disease Outcomes Quality Initiative (KDOQI),⁷ believe that local factors require consideration when making recommendations to guide care. As such, the CSN guidelines committee formed a work group to evaluate the KDIGO CKD-MBD guidelines and determine the extent to which they were relevant within a Canadian context. This CSN work group believes that any limitations of these guidelines relate not to the effort of the KDIGO work group, but to the lack of information for the significance of mineral metabolism abnormalities in early-stage CKD, and more specifically, to the lack of conclusive information about how to guide management throughout CKD stages 3-5.

The KDIGO CKD-MBD guidelines focus on the management of children and adults with nondialysis and dialysis CKD and patients with kidney transplants. Given that the focus of the CSN is adults with CKD and the Canadian Society of Transplantation is preparing a commentary on the transplant-specific CKD-MBD guidelines, this commentary focuses on KDIGO guidelines relevant to adults with nondialysis and dialysis CKD. While preparing this commentary, the CSN work group carefully considered 2 recent Canadian sets of guidelines that have addressed mineral metabolism in CKD. These include: (1) the 2006 CSN hemodialysis guidelines,⁸ which had a target audience of Canadian nephrologists and addressed the management of mineral metabolism in dialysis patients with CKD; and (2) the 2008 CSN guidelines focusing on the overall management of patients with nondialysis CKD targeting general practitioners.⁹ Although the present commentary focuses on the KDIGO guidelines, important differences between the KDIGO CKD-MBD recommendations and the relevant CSN guidelines, as well as the reasons for these discrepancies, are noted when applicable.

Although this commentary is most relevant to Canadian nephrologists and specialists who care for patients with dialysis and nondialysis CKD, some of the commentary may be relevant for general practitioners who care for patients with CKD. In general, the CSN work group is of the opinion that CKD-MBD care should not be undertaken by general practitioners; rather, their focus should continue to be on therapies that have proven efficacy in patients with CKD, including cardiovascular risk reduction.

Across the Canadian health care jurisdictions, there is variable but highly restricted access to public funding for expensive medications (including non–calcium-based phosphate binders and calcimimetics), reflecting their high cost and limited outcome data beyond putative surrogate end points.¹⁰ Acknowledging this reality and to maintain consistency with previous CSN guidelines, the resource implications of guidelines were considered when preparing this commentary.¹ The rationale for this is as follows. Given that the budget for health care is finite, directing excessive resources toward expensive marginally effective therapies limits the resources available to be used for other effective therapies.¹¹, ¹² In many Canadian jurisdictions, renal programs are responsible for caring for a defined group of dialysis and selected nondialysis patients with CKD with a finite pool of resources.¹⁰ Careful consideration of both an intervention's effectiveness (and the magnitude of effect) and cost is needed to deploy resources to maximize health outcomes for our patients. Because physicians often are in a position to compare the benefits and risks of specific therapies, they should take an active role in deciding which therapies should be made available, by reimbursement, to Canadian patients.

Having said that, an alternate point of view expressed within the CSN is that as nephrologists, we are advocates for our patients, and failure to champion promising therapeutic interventions will lead to inadequate access to novel strategies.¹³, ¹⁴ This viewpoint may be influenced by the poor outcomes for dialysis patients and the belief that strict adherence to principles of evidence-based medicine is limited by the paucity of well-performed randomized controlled trials.¹⁵ In the opinion of this CSN workforce, the KDIGO guidelines in general considered these issues and crafted recommendations that generally were acceptable, avoiding overly prescriptive recommendations when evidence was not definitive. Although this approach may be criticized, the reality is that nephrology has the fewest randomized trials of any medical subspeciality,¹⁵ leading to a slim evidence base available to guide therapy. There is a lack of definitive evidence for potentially promising therapies, and this has led to variation in perspectives of Canadian nephrologists, as well as variation in access to therapies in Canada. The workforce strongly believes that nephrology as a community needs to focus its academic pursuits on improving the nephrology evidence base, and this should be done in partnership with industry and nonindustry funding agencies.

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Review and Approval Process for CSN Guidelines and Commentaries 

The development and review of this commentary were consistent with CSN policies set out for the conduct of clinical practice guidelines. The CSN guideline committee determined that this commentary was of priority, and a Chair was selected to guide the commentary process. Individual members were selected based on their interest and expertise, taking into consideration relevant conflicts of interest. Commentary development took place during fall 2009 using the original KDIGO CKD-MBD guidelines,⁶ as well as the primary documents referenced within this report; additional literature searching was left to the discretion of individual members. After repeated teleconferences, all authors approved the final text of the commentary. Because this was a commentary rather than a guideline, consensus was sought, and when it could not be achieved, both perspectives are raised. The final document was sent out for peer review by the CSN guidelines committee. The reviews were considered and responded to, with incorporation of further revisions before ratification by the CSN guidelines committee and CSN executive.

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Structure of This Commentary 

This commentary does not seek to discuss all KDIGO recommendations; rather, it was our intent to focus commentary on recommendations that are based on better quality evidence (ie, level 1 in the guideline⁶) or are more controversial. The KDIGO recommendations are provided in boxes, with CSN concurrence indicated. Implications and commentary relevant for Canadian health care are offered in the text when appropriate. For some recommendations (typically those that are opinion based), specific comments are not provided in italics.

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Review of KDIGO Recommendations 

Diagnosis of CKD-MBD: Biochemical Abnormalities 

In chapter 3.1, there are 3 level 1 recommendations (Box 1). Our work group believed that one recommendation deserved further discussion; namely, the statement “We recommend monitoring serum levels of calcium, phosphorus, PTH [parathyroid hormone], and alkaline phosphatase activity beginning in CKD stage 3 (1C)” and the suggested monitoring intervals of every 6-12 months in stage 3 CKD. Given that the frequency of abnormalities in serum calcium and phosphorus levels is rare at a glomerular filtration rate (GFR) >40 mL/min (almost no patients with GFR >40 mL/min in a cross-sectional analysis of more than 1,800 patients with CKD stages 3-5 patients had abnormal calcium or phosphorus levels¹⁶), it is difficult to present a substantive argument in favor of routine measurement of calcium and phosphorus in patients with stage 3 CKD. This is particularly true given that the impact of managing abnormalities in mineral metabolism in patients with stage 3 CKD is unknown, and most patients will not go on to require dialysis, but instead will die of other causes.¹⁷ Moreover, when one considers that >95% of Canadian patients with stages 3-5 nondialysis CKD have stage 3 CKD,¹⁸ this recommendation may inadvertently direct attention to a cohort of patients without identifiable laboratory abnormalities.

Of note, one other recommendation (level 2C) suggested that “25(OH)D (calcidiol) levels might be measured, and repeated testing determined by baseline values and therapeutic interventions.” It was noted that the cost of laboratory tests, particularly measurement of PTH and vitamin D, is significant, and given budget limitations within publicly funded Canadian health care, this could direct resources away from other treatments for which better evidence of benefit is available. For example, the cost of a serum 25-hydroxyvitamin D assay is Can $100 locally. Until the clinical benefit of correcting nutritional vitamin D “insufficiency” has been established within the dialysis population or for patients with stages 4 and 5 CKD, it would seem premature to suggest screening with vitamin D assays. For patients with stage 3 CKD without biochemical evidence of MBD, it is reasonable to expect that the overall benefits of vitamin D supplementation in the general population (800-2,000 U/d) would apply, and Osteoporosis Canada does not recommend screening 25-hydroxyvitamin D assays in the general population for individuals already using routine supplementation.¹⁹

Diagnosis of CKD-MBD: Bone 

Fractures are more prevalent in patients with CKD stage 5 contrasted with the nonuremic population.⁶ This is particularly true of hip fractures in elderly dialysis patients, particularly those with diabetes. The KDIGO working group found little evidence that future fracture risk might be linked specifically to identifiable risk factors or modified by specific therapy. The CSN work group agrees that it is not possible to generalize the extensive epidemiologic characteristics of fractures (and evidence-based therapy) in the general population to patients with CKD.

The diverse spectrum of the metabolic bone disease associated with renal osteodystrophy ranges from extensive deposits of woven bone in hyperparathyroidism to excessive unmineralized osteoid associated with osteomalacia; “adynamic” bone is more normal in structure. Not surprisingly, both bone mass and bone quality within the skeleton can vary widely according to the underlying pathobiological process. For this reason, the KDIGO working group emphasized at several points that bone biopsy with histomorphometric evaluation is the only certain method of classifying the underlying bone disease.

Bone mineral density (BMD) measurements assume a stable ratio of calcium hydroxyapatite to organic matrix within bone to assess “bone mass.” In the general population, this relationship is valid enough that a diagnosis of osteoporosis can be made using the World Health Organization T score of −2.5 standard deviations less than “peak adult bone mass.”²⁰ Moreover, the combination of age, BMD, and specific additional risk factors (particularly prevalent osteoporotic fractures) allows some prediction of the probability of future fractures in the next 10 years, as recommended by Osteoporosis Canada.²¹ However, BMD generally is lower in the dialysis population, particularly at cortical measurement sites (distal radius and hip), and the ability of BMD to predict fractures or other clinical outcomes in dialysis patients is weak and inconsistent. Moreover, in patients with nondialysis CKD stages 3-5 associated with abnormalities in mineral metabolism and dialysis CKD, BMD measurements do not distinguish between histologic types of underlying renal osteodystrophy. For these reasons, we agree that BMD measurements should not be used as a diagnostic tool in CKD stages 3-5 (Box 2). However, it is reasonable to conclude that decreased BMD in patients with stage 3 CKD without biochemical evidence of MBD can still be used to diagnose underlying osteoporosis.

Diagnosis of CKD-MBD: Vascular Calcification 

The CSN work group noted that chapter 3.3 referred to patients with stages 3-5 nondialysis and dialysis CKD (Box 3).⁶ However, it is important to emphasize that the level of evidence, prevalence, and therapeutic strategies are heterogeneous among the various CKD stages, and most evidence exists for dialysis CKD.

With respect to the first recommendation, it is true that a lateral abdominal radiograph and 2-dimensional echocardiogram may be used to detect vascular and valvular calcification. However, it is important to note that population screening is not recommended by KDIGO or existing CSN guidelines because there are many unanswered questions regarding the utility of screening and lack of therapies conclusively shown to improve clinical outcomes in patients with vascular calcification or even treat and/or prevent vascular and valvular calcification.

With regard to the second recommendation, we note that all patients with CKD have increased cardiovascular risk. We agree that patients with vascular/valvular calcification carry an added adverse cardiovascular risk, although there is a large range of risk profile in patients with nondialysis and dialysis stages 3-5 CKD.

Treatment of CKD-MBD Targeted at Lowering High Serum Phosphorus and Maintaining Serum Calcium 

Most recommendations in Chapter 4.1 are opinion based (Box 4). With respect to the recommendation regarding dialysate calcium concentration, the work group believed there may be selected situations in which a lower or higher dialysate calcium concentration may be considered after careful assessment of risks and benefits. For example, a low (1.0 mmol/L) bath may be considered in selected patients with hypercalcemia, although the risks associated with hypercalcemia need to be balanced against the potential risks of intradialytic hypotension and propensity toward arrhythmia.²² Also, higher calcium concentration could be considered in nocturnal dialysis patients, who are more likely to have a net negative calcium balance,²³ or after parathyroidectomy, when “hungry” bones can cause refractory hypocalcemia. It should be noted that the impact of these strategies on clinical outcomes and the safety of low calcium baths (<1.25 mmol/L) are uncertain (as for all strategies discussed next), although selecting a different calcium dialysate typically will have no impact on costs.

One level 1 recommendation (to restrict the dose of calcium-based phosphate binders and/or dose of calcitriol or vitamin D analogue in the presence of persistent hypercalcemia) stimulated much discussion (Box 4). Although level 1, this recommendation is based on more common sense and observational data than randomized trials. The CSN work group acknowledged that based on the available evidence, limiting calcium intake in the scenarios described is likely to be more beneficial than harmful, although there was no consensus about the best strategy to achieve such a recommendation (discussed next).

There is a clear epidemiologic association and biological plausibility among hyperphosphatemia, net calcium intake, and important negative health consequences for patients with CKD that was shown first in a study of pediatric dialysis patients.²⁴ However, there is a lack of randomized trial evidence to suggest that maintaining serum calcium and phosphorus levels within the reference range is associated with improvements in clinically important outcomes.²⁵ Additionally, randomized controlled trials and meta-analyses performed to date do not conclusively support the use of one type of phosphate binder in preference to another for important patient outcomes.²⁵, ²⁶, ²⁷, ²⁸

Specifically, controversy exists about the efficacy of non–calcium-based phosphate binders (ie, sevelamer and lanthanum) on relevant clinical outcomes (cardiovascular events, mortality, and hospitalization). The largest clinical trial to date, the Dialysis Clinical Outcomes Revisited (DCOR) study, enrolled 2,103 prevalent dialysis patients, allocating patients to sevelamer or calcium therapy.²⁵ Although follow-up lasted for 20 months on average, this study had significant method limitations, including a differential loss to follow-up of approximately 50% in both groups and lack of patient blinding. The primary analysis showed no difference in patient survival between study groups (hazard ratio, 0.93 [95% confidence interval, 0.79-1.10]), although secondary analyses suggested a decrease in mortality in patients older than 65 years.²⁵ Reanalysis of this data set using Medicare claims data (thus ensuring complete follow-up for the primary outcome) showed no difference in mortality overall or in any patient subgroup.²⁹ One small randomized study of incident dialysis patients suggested improved survival, although this was noted in only adjusted analyses and after extended follow-up after active treatment and the planned study period had ended.³⁰ Three meta-analyses have compared the impact of non–calcium-based phosphate binders and calcium-based phosphate binders on mortality. One found no difference in survival,²⁶ whereas 2 found a non–statistically significant 30% decrease in mortality.²⁷, ²⁸ Given the methodological limitations and therefore concern for study validity for the largest trials contributing weight to these meta-analyses (including significant loss to follow-up; ie, >50% in the largest sevelamer and lanthanum trials,²⁵, ³¹ and lack of patient blinding), the impact of non–calcium-based binders on clinically relevant outcomes is uncertain.

Given how common vascular calcification is in dialysis patients, many cases are likely to be detected incidentally. In patients with arterial calcification and hyperphosphatemia, KDIGO recommends restricting the dose of calcium-based phosphate binders. Presumably, implementation of this recommendation may require the use of more frequent dialysis or of much longer duration or the use of non–calcium-based phosphate binders, which are more than 20-fold more expensive than calcium carbonate. If the cost of non–calcium-based phosphate binders was similar to that of calcium-based binders, our work group believed that use of such binders would be much less controversial. However, this is not the case.

The recommendation by KDIGO to limit the use of calcium-based binders in the scenarios outlined (and presumably use non–calcium-based binders) generated significant discussion, and our work group could not reach consensus. Given the lack of conclusive evidence of benefit, the lack of randomized trials that have assessed morbidity and mortality in patients with vascular calcification, and the expense of sevelamer and lanthanum, several members believed that use of these agents was not justified until further evidence of clinical benefit could be established in valid randomized trials. Moreover, these members believed that such a recommendation would make it less likely that the randomized trials needed to investigate the efficacy of these agents would be performed. Given the recent drawn-out experience with hemoglobin normalization in patients with end-stage renal disease,³² largely supported by similar lines of observational evidence, this situation is far from optimal.

Alternatively, other members believed that the use of non–calcium-based binders in the situations recommended or suggested by KDIGO was justified on theoretical grounds, the existing randomized controlled trials were underpowered to show statistically significant benefit, recent meta-analyses suggest clinical benefit, and calcium-based phosphate binders are likely to cause positive calcium balance in late stages of CKD and have never been proven to be safe.

Treatment of Abnormal PTH Levels in CKD–MBD 

Within this section, there is only one relatively strong recommendation, that “vitamin D sterols or calcitriol be reduced or stopped in patients with hypercalcemia,” with the rest of the recommendations being based on weak evidence (Box 5). In contrast to previous KDOQI guidelines on mineral metabolism,³³ these guidelines are much less prescriptive and do not provide specific targets for therapy other than to suggest an intact PTH level of 2-9 times the reference range. The KDIGO guidelines are similar to the CSN guidelines,⁸ emphasizing the importance of increased phosphate and calcium levels rather than PTH levels.

Although some clinicians may believe that the present KDIGO guidelines are not helpful in patient management, the following points should be emphasized: (1) the level or range of intact PTH levels that are associated with or determine bone health or cardiovascular health are unknown; (2) increased PTH levels have been associated with cardiovascular events, but the association is not as strong as for hyperphosphatemia and there are no randomized trials that have shown decreasing PTH levels to be associated with better clinical outcomes; (3) low PTH levels seem to be as common, if not more common, than increased levels, and options for reversing this or the implications of such a reversal are not well worked out; and (4) previous studies of vitamin D, vitamin sterols, and calcimimetics in patients with CKD have either been of poor quality and/or have used biomarkers as the study outcomes, rather than clinical end points.

Treatment of Bone With Bisphosphonates, Other Osteoporosis Medications, and Growth Hormone 

Dialysis patients who present with intercurrent fractures present a particular therapeutic dilemma because fractures are common and there is no evidence to date that any therapy decreases the risk of fracture in dialysis patients. With respect to nondialysis CKD, the CSN work group noted that post hoc analyses of the pivotal clinical trials evaluating antiresorptive therapies allow some recommendations concerning these agents in managing osteoporosis in patients with impaired kidney function. In patients with CKD stages 1-2, there is good evidence that the efficacy of bisphosphonates and raloxifene is not impaired. The same can be said of these agents in patients with CKD stage 3, provided that these individuals have no underlying biochemical evidence of CKD-MBD. These recommendations follow from the post hoc analyses of pivotal phase 3 randomized clinical trials of these agents, in which patients were enrolled with various degrees of kidney disease (though all participants were required to have normal biochemical parameters of vitamin D and parathyroid function). Thus, the CSN work group agrees that management of future fracture risk reduction should be no different in these patients than for the general population (Box 6).

In patients with advanced stage 3 CKD with evidence of biochemical abnormalities in mineral metabolism, as for patients with stages 4 and 5 CKD, the work group could find little evidence on which to base therapeutic recommendations (Box 6). There are no data to support either the safety or the efficacy of bisphosphonates, estrogens, or selective estrogen receptor modulators to prevent fractures in this population.

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Conclusion 

In many ways, nephrologists should be chagrined by the situation we find ourselves in when attempting to care for dialysis patients in general and in particular with respect to mineral metabolism. It is clear that abnormalities in mineral metabolism are associated with adverse clinical outcomes. However, our management is driven largely by results of observational trials because the number of clinical trials is limited and existing clinical trials often are underpowered or use nonclinical outcomes.

Future changes in care should be driven by adequately powered randomized trials with clinical end points. The challenge is to create an environment that promotes advances in CKD care, stimulates randomized trials, increases evidence-based nephrology practice, and encourages industry and public research funders to support this. Moreover, it important to satisfy provincial health ministries that nephrologists are reasonable in terms of balancing access to promising new treatments while acknowledging that resources directed to therapies with an incomplete evidence-base might direct resources away from other effective therapies. Perhaps a more general discussion of how to accomplish these goals for our data-impoverished discipline should take priority over the production of specific guidelines for the time being. Specifically, the nephrology community must be a willing partner in conducting randomized trials and create a culture that stimulates and values the production and implementation of such research.

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Acknowledgements 

Support: No financial support was required for the development of this commentary.

Financial Disclosure: In the interest of transparency and full disclosure, the Appendix includes conflict-of-interest information for all members of the work group.

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Appendix 

Conflict of Interest Information for Work Group Members

Note: Information provided concerns the past 3 years.

Abbreviation: CSN, Canadian Society of Nephrology.

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