Mineral and Bone Disorders in CKD – New KDIGO Update

What’s the latest evidence affecting clinical management of mineral and bone disorder in chronic kidney disease? Updated recommendations by the Kidney Disease: Improving Global Outcomes (KDIGO) Global Network are now available.

The 2017 KDIGO Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) guideline update has implications for diagnosis, evaluation, prevention, and treatment of secondary CKD-MBD in children and adults. The full guideline has been published as a supplement to Kidney International; an Executive Summary appears in the July issue of Kidney International.

Updating the previous guideline published in 2009, the revision reflects new research related to management of CKD-MBD. In a key change, it recommends against routine use of calcitriol or vitamin D analogs for treatment of abnormal parathyroid hormone (PTH) levels.

That change reflects a continued lack of data on the optimal PTH level for patients with CKD G3a to G5. Meanwhile, the 2017 Update Working Group believes that modest rises in PTH may be an “appropriate adaptive response” to decreased kidney function.

“Randomized controlled trials have not really shown a benefit and perhaps harm because of hypercalcemia,” said Michael J. Germain, MD, Professor of Medicine, Tufts University School of Medicine and Nephrologist/Partner, Western New England Renal & Transplant Associates, PC, Springfield, Mass. Calcitriol and vitamin D analogs “do a good job in terms of suppressing PTH, but they haven’t shown a benefit in terms of other outcomes, [including] cardiovascular outcomes.”

The update suggests that calcitriol and vitamin D analogs “not be routinely used” in adults with CKD G3a-G5 not on dialysis. Although there was no “uniform consensus” regarding this recommendation, it reflects a lack of data showing benefits of these older drugs on patient-level outcomes.

The revised guideline mentions a potential new alternative for secondary hyperparathyroidism. Extended-release (ER) calcifediol (Rayaldee) was recently approved for use in adults with stage 3 or 4 CKD and serum total 25-hydroxyvitamin D less than 30 ng/mL. Approval was based on trials showing that ER calcifediol reduced intact PTH while increasing 25D. Effects on calcium and phosphorus were similar to placebo.

“This is a medication that can be used in predialysis patients,” said Dr. Germain. “It has the advantage, as opposed to the activated vitamin Ds, of doing a good job in replacing nutritional 25D in the body and normalizing the blood level. By its mechanism of action, it does prevent catabolic pathways from breaking down vitamin D.” The data on ER calcifediol were published after the KDIGO evidence review, and do not include patient-level outcomes.

Extended-release calcifediol is not indicated for dialysis patients. OPKO, manufacturer of Rayaldee, states that it “plans to start a Phase 2 trial in dialysis in partnership with Vifor by the end of the year.”

Dr. Germain notes that calcimimetics are “a reasonably good treatment” for the more severe hyperparathyroidism seen in dialysis patients. He points out that the intravenous calcimimetic etelcalcetide (Parsabiv) was approved for use in dialysis patients earlier this year.

An updated recommendation states that it’s “reasonable” to reserve calcitriol and vitamin D analogs for patients with CKD G4-G5 with severe progressive hyperparathyroidism. In children, these drugs “may be considered” to maintain serum calcium in the normal range for age.

Other revised recommendations address:

CKD-MBD Diagnosis. Recent studies have added evidence that measuring bone mineral density (BMD) predicts fractures in patients with CKD, as in the general population. On that basis, BMD assessment is suggested to assess fracture risk in CKD G3a-G5D, if the results will affect treatment decisions.

Bone biopsy is considered “reasonable” if information on the type of renal osteodystrophy will affect treatment. Dr. Germain cites that recommendation as an example of how guidelines based on literature reviews may provide limited guidance for nephrologists in practice. “The problem is that very few people can get biopsies” due to the lack of specialized pathology personnel and equipment. “If [KDIGO] are going to recommend [bone biopsy], they really have to acknowledge the fact that it’s impossible to get for probably 95% to 99% of nephrologists.”

Serum phosphate and calcium. Recent studies have linked higher serum phosphate levels to increased mortality, but there’s still a lack of evidence that phosphate-lowering therapy improves patient outcomes. The revised guideline removes a previous recommendation to maintain phosphate in normal range, instead focusing on treatment for hyperphosphatemia. It also discusses new data on calcium-containing versus calcium-free phosphate binders.

Antiresorptive and other osteoporosis therapies. Recommendations for antiresorptive and other osteoporosis treatments were broadened from CKD G3a-G3b to G3a-G5d. Treatment choices should consider specific side effects and the accuracy of the underlying diagnosis.

Kidney transplant bone disease. The update addresses the use of BMD testing to assess fracture risk. Evidence supports treatment suggestions for the first 12 months, but not thereafter.

The KDIGO Working Group notes that its updated guideline still reflects a “dearth of high-quality evidence…in several areas pertaining to CKD-MBD.”

Research priorities “need to be very focused on the patient’s experience,” Dr. Germain believes. “I would concentrate more on bone health and what the patient experiences, so they feel better.” He thinks that nephrologists treating MBD need to “know a little bit more about what the patient’s symptoms are in dialysis and what could be related to the hyperparathyroidism.

“And then, does treatment actually improve their symptoms and their day-to-day life?” He emphasizes the need for studies focusing on patient-reported outcomes and giving patients more choices and input into treatment decisions—notably including choices about phosphate binder therapy.

"September 2017 (Vol. 9, Number 9)"

Suggested Reading

1. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2017; 7:1–59.

2. Ketteler M, et al: Executive summary of the 2017 KDIGO Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Guideline Update: what’s changed and why it matters. Kidney Int. 2017; 92:26–36.

3. Sprague SM, et al: Use of extended-release calcifediol to treat secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease. Am J Nephrol. 2016; 44:316–325.