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    Suggested algorithm for fracture risk screening and initiation of anti-fracture strategies in patients with CKD

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    Suggested algorithm for management of fractures

  • 1.

    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; 76 (Suppl 113): S1130.

    • Search Google Scholar
    • Export Citation
  • 2.

    Ketteler M, et al. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. Kidney Int Suppl 2017; 7[Suppl 1]:159.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Khairallah P, Nickolas TL. Management of osteoporosis in CKD. Clin J Am Soc Nephrol 2018; 13:962969.

  • 4.

    Pimentel A, et al. Fractures in patients with CKD—diagnosis, treatment, and prevention: A review by members of the European Calcified Tissue Society and the European Renal Association—European Dialysis and Transplant Association. Kidney Int 2017; 92:13431355.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Isakova T, et al. Longitudinal FGF23 trajectories and mortality in patients with CKD. J Am Soc Nephrol 2018; 29:579590.

  • 6.

    Ross AC, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 2011; 96:5358.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Levin A, et al. Randomized controlled trial for the effect of vitamin D supplementation on vascular stiffness in CKD. Clin J Am Soc Nephrol 2017; 12:14471460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Kumar V, et al. A randomized trial of vitamin D supplementation on vascular function in CKD. J Am Soc Nephrol 2017; 28:31003108.

  • 9.

    Courbebaisse M, et al. Non-skeletal and skeletal effects of high doses versus minimum recommended intake of vitamin D3 in renal transplant recipients in a prospective, multicenter, double-blind, randomized study. Late Breaking Clinical Trial Abstract, ERA-EDTA Congress 2019, Budapest.

    • Search Google Scholar
    • Export Citation
  • 10.

    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; 44:316325.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Strugnell SA, et al. Rationale for raising current clinical practice guideline target for serum 25-hydroxyvitamin D in chronic kidney disease. Am J Nephrol 2019; 49:284293.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Cozzolino M, Ketteler M. Evaluating extended-release calcifediol as a treatment option for chronic kidney disease-mineral and bone disorder (CKD-MBD). Expert Opin Pharmacother. 2019; 20: 2081-2093.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Scragg R, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study: A randomized clinical trial. JAMA Cardiol 2017; 2:608616.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Scragg R, et al. Monthly high-dose vitamin D supplementation and cancer risk: A post hoc analysis of the vitamin D assessment randomized clinical trial. JAMA Oncol 2018; 4:e182178.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Manson JE, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 2019; 380:3344.

  • 16.

    de Boer IH, Zelnick LR, Ruzinski J, et al. Effect of vitamin D and omega-3 fatty acid supplementation on kidney function in patients with type 2 diabetes: A randomized clinical Trial. JAMA. 2019; doi: 10.1001/jama.2019.17380.

    • Crossref
    • Search Google Scholar
    • Export Citation

Chronic Kidney Disease–Mineral and Bone Disorder: Personal Perspective after the 2017 KDIGO CKD-MBD Guideline Update

  • 1 Markus Ketteler, MD, FERA, is the head of the Department of General Internal Medicine and Nephrology, Robert Bosch Hospital, Stuttgart, Germany.
Full access

The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) represented a selective update of the prior CKD-MBD guideline published in 2009 (1, 2). The guideline update, along with the original 2009 publication, is intended to assist physicians, especially nephrologists, who care for CKD patients, including those using long-term dialysis therapy and individuals with a kidney transplant.

The 2017 guideline update focused on recommendations for the diagnosis of bone abnormalities in CKD-MBD; treatment of CKD-MBD by lowering serum phosphate and maintaining serum calcium; treatment of parathyroid hormone abnormalities in CKD-MBD; treatment of bone abnormalities by the use of antiresorptive agents and other osteoporosis therapies; and the evaluation and treatment of kidney transplant bone disease.

Although a reasonable number of high-quality studies were published between 2009 and 2017, significant gaps in the knowledge base about the optimized treatment approaches for patients with features of CKD-MBD still exist. Nevertheless, I would like to briefly feature three developments that were stimulated by the recent KDIGO CKD-MBD update publication that may improve the treatment of patients in the future, at least from my subjective point of view:

  • ■ Diagnosis and management of osteoporosis in CKD patients

  • ■ Fibroblast growth factor-23 (FGF23) as a biomarker

  • ■ Role of nutritional vitamin D in CKD

Osteoporosis in CKD

Among the most prominent changes in the 2017 guideline update were recommendations about the clinical handling of suspected osteoporosis in patients in all stages of CKD. First, dual-energy X-ray absorptiometry for determining bone mineral density became recommended as a reasonable diagnostic test for assessing fracture risk, if the results may affect treatment decisions. Second, the caution and reservation against classic anti-osteoporosis medications (especially antiresorptive agents) was partially relieved by the accumulating evidence supporting potential clinical benefits under defined circumstances.

The KDIGO update release was consequently followed by the publication of two remarkable and well-balanced review articles that both presented clinical algorithms for two different settings:

  1. Patients in all stages with low bone mineral density (T score ≤2.5), or with T score >2.5 plus a low-impact fracture according to the World Health Organization’s definition of osteoporosis (3)

  2. Dialysis patients (CKD G5D) with low-impact fractures (4)

The first algorithm (Figure 1) suggested using cutoff levels of bone-specific alkaline phosphatase as a pragmatic approach to more appropriately stratifying patients into high, normal, or low bone turnover groups, and it assigned treatment modalities accordingly (3). In essence, proper management of CKD-MBD phenotypes is warranted before more specific therapeutic approaches should be considered.

Figure 1.
Figure 1.

Suggested algorithm for fracture risk screening and initiation of anti-fracture strategies in patients with CKD

Citation: Kidney News 12, 1

Abbreviations: CKD-MBD, chronic kidney disease-mineral and bone disorder; DXA, dual-energy X-ray absorptiometry; GFR, glomerular filtration rate; PTH, parathyroid hormone. Reprinted from Khairallah P et al. (3) with permission.

The second algorithm (Figure 2) for dialysis patients suggested a two-step approach, based on three groups of intact parathyroid hormone levels in accordance with the KDIGO guideline recommendations, followed again by ascertaining serum concentrations of bone-specific alkaline phosphatase (4). Both reviews also quite pragmatically discussed and considered the potential of bone biopsy in their management schemes. Although these publications obviously reflect the authors’ opinions, they appear to provide rather sensible advice about issues for which the data are limited.

Figure 2.
Figure 2.

Suggested algorithm for management of fractures

Citation: Kidney News 12, 1

Abbreviations: BSAP, bone-specific alkaline phosphatase; PTH, parathyroid hormone; ULN, upper limit of normal; VRDA, vitamin D receptor activators. Reprinted from Pimentel A, et al. (4) with permission.

Biomarker FGF23

One of the most interesting but challenging issues in CKD-MBD is the role of FGF23 as a diagnostic biomarker or even a therapeutic target. It seems quite evident that this phosphatonin is crucial in the regulation of phosphate and vitamin D homeostasis in progressive CKD, especially in earlier stages, but it might also develop into a cardiovascular threat for patients, owing to possible myocardial toxicity.

A recent article suggested that absolute FGF23 serum levels may be of secondary importance concerning risk prediction, especially in CKD patients not receiving dialysis, in comparison with the dynamics and trends of this biomarker (so-called trajectories) (5). By far, the highest risk prediction was observed when FGF23 levels rapidly rose over time, in contrast to slowly rising or stable FGF23 serum concentrations. This observation might potentially qualify FGF23 as a longitudinal marker of CKD severity and cardiovascular consequences. In this context, further insights about the power of available medications to substantially lower FGF23 blood levels (e.g., calcimimetics, phosphate binders) may thus have an impact on treatment modalities if FGF23 lowering can be proved to associate with improved patient-meaningful outcomes in randomized controlled trials.

Management of vitamin D status

The current recommendations about vitamin D deficiency and insufficiency from the original KDIGO CKD-MBD 2009 guidelines remain oriented toward targets for the normal population as published by most osteoporosis societies and the Institute of Medicine (6). The latter position paper recommended a range of 25-hydroxy-vitamin D levels between 20 and 60 ng/mL as necessary to achieve, and it emphasized the importance of vitamin D for bone health while remaining cautious about the so-called pleiotropic effects on cancer and cardiovascular disease protection, infectious diseases, or autoimmunity.

Nevertheless, this unsolved issue triggered a few new study approaches that demonstrated the potentially beneficial effects of high-dose vitamin D3 supplementation with regard to endothelial function and vascular stiffness (7, 8). As reported at the recent ERA-EDTA Congress 2019 in Budapest, the VITALE study found that high-dose vitamin D3 treatment was associated with a lowered risk of symptomatic fracture (1% vs. 4% in low dose, odds ratio = 0.24, p = 0.02) in kidney transplant recipients, although other major study endpoints (cardiovacular events, diabetes incidence, cancer, death) were not reached (9). Further, the results of treatment studies in which extended-release calcifediol was used revealed that levels of 25-hydroxy-vitamin D between 50 and 80 ng/mL—even higher than those recommended by the Institute of Medicine (IOM)—are required to effectively control secondary hyperparathyroidism in CKD patients not using dialysis (10-12).

Recently, however, two large randomized controlled trials (ViDa [n = 5108], VITAL [n = 25,871]) failed to demonstrate beneficial effects on cardiovascular and cancer endpoints by high-dose vitamin D3 supplementation in the normal population (1315). Both trials potentially suffered from the fact that most patients were not in a state of vitamin D deficiency at baseline (actually levels at both baseline and the end of study were within the IOM recommended range in the two trials). A recent subgroup analysis of VITAL (VITAL-DKD) in patients with type 2 diabetes mellitus (n = 1,312) reported no significant difference in the change of estimated glomerular filtration rate with vitamin D supplementation (16). Nonetheless, follow-up periods of 3 or 5 years may still be too short to enable credible conclusions to be reached. It is hoped that further post hoc analyses of subgroups with impaired kidney function may become available from these trials, enabling an informative view on vitamin D supplementation in CKD patients.

Perspective

Guideline publications are always a chance and a challenge. Unanswered questions still need to be pragmatically addressed, and if this is preliminarily done by balanced expert opinion, it will be of great help for the practitioner. When research questions are raised, knowledge gaps may be subsequently closed one by one. In about 3 years from now, the CKD-MBD field will have yet again to be reappraised concerning the accumulated evidence so that ever more sustainable advice can be generated for clinical decision-making.

References

  • 1.

    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; 76 (Suppl 113): S1130.

    • Search Google Scholar
    • Export Citation
  • 2.

    Ketteler M, et al. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. Kidney Int Suppl 2017; 7[Suppl 1]:159.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Khairallah P, Nickolas TL. Management of osteoporosis in CKD. Clin J Am Soc Nephrol 2018; 13:962969.

  • 4.

    Pimentel A, et al. Fractures in patients with CKD—diagnosis, treatment, and prevention: A review by members of the European Calcified Tissue Society and the European Renal Association—European Dialysis and Transplant Association. Kidney Int 2017; 92:13431355.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Isakova T, et al. Longitudinal FGF23 trajectories and mortality in patients with CKD. J Am Soc Nephrol 2018; 29:579590.

  • 6.

    Ross AC, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 2011; 96:5358.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Levin A, et al. Randomized controlled trial for the effect of vitamin D supplementation on vascular stiffness in CKD. Clin J Am Soc Nephrol 2017; 12:14471460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Kumar V, et al. A randomized trial of vitamin D supplementation on vascular function in CKD. J Am Soc Nephrol 2017; 28:31003108.

  • 9.

    Courbebaisse M, et al. Non-skeletal and skeletal effects of high doses versus minimum recommended intake of vitamin D3 in renal transplant recipients in a prospective, multicenter, double-blind, randomized study. Late Breaking Clinical Trial Abstract, ERA-EDTA Congress 2019, Budapest.

    • Search Google Scholar
    • Export Citation
  • 10.

    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; 44:316325.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Strugnell SA, et al. Rationale for raising current clinical practice guideline target for serum 25-hydroxyvitamin D in chronic kidney disease. Am J Nephrol 2019; 49:284293.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Cozzolino M, Ketteler M. Evaluating extended-release calcifediol as a treatment option for chronic kidney disease-mineral and bone disorder (CKD-MBD). Expert Opin Pharmacother. 2019; 20: 2081-2093.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Scragg R, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study: A randomized clinical trial. JAMA Cardiol 2017; 2:608616.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Scragg R, et al. Monthly high-dose vitamin D supplementation and cancer risk: A post hoc analysis of the vitamin D assessment randomized clinical trial. JAMA Oncol 2018; 4:e182178.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Manson JE, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 2019; 380:3344.

  • 16.

    de Boer IH, Zelnick LR, Ruzinski J, et al. Effect of vitamin D and omega-3 fatty acid supplementation on kidney function in patients with type 2 diabetes: A randomized clinical Trial. JAMA. 2019; doi: 10.1001/jama.2019.17380.

    • Crossref
    • Search Google Scholar
    • Export Citation
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