Conclusions and future directions: ‘The known unknowns ….’

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This monograph has aimed to present a detailed discussion regarding the complex problems of chronic kidney disease‐mineral and bone disorder (CKD‐MBD) along with thoughtful commentary regarding current and proposed guidelines for managing these conditions. The issues are readily apparent: Patients with CKD die from the intricate and intermeshed components of kidney, bone and vascular disease. Clinicians care for these individuals to the best of their ability; but, as outlined in each chapter, do so with a pressing awareness of the significant gaps in evidence that might otherwise inform optimal management of the people and pathology confronting them. Critical and timely decisions have to be made – but without all the relevant information.
What is also apparent, though, is that the known knowns regarding CKD‐MBD and its management are slowly increasingly. Predictably, an increase in the known unknowns accompany each step. It is illuminating to consider the differences between the two main sections of this supplement, under the headings of investigations and therapeutics. Since the first iteration of the Kidney Disease Improving Global Outcomes (KDIGO) CKD‐MBD guidelines, significant gains have been made in the former, but without much improvement in the latter.
It was a known known that “a lack of robust screening tools for [renal osteodystrophy] has …. limited our ability to develop therapeutic options and conduct appropriate interventional trials” (Drs Sharma and Toussaint). It is clear from the submissions that there has been improvement in such screening tools. They remain imperfect, but they are better.
There has been considerable progress in the understanding of mechanisms underlying vascular calcification (VC), and there are newer and more accurate means of assessing this. But how VC information can be best used to stratify risk, and whether any therapeutic intervention makes a difference to VC and to patient outcomes is not known.
It is known that a bone biopsy provides extremely robust information about the skeleton at the point of biopsy, but it is also known that it only provides a snapshot of one area of the skeleton at one point in time. How to capture the rest of the skeleton is still an unknown. HRqCT and microMRI might prove useful, non‐invasive, and more accessible alternatives. These too, though, only provide information about the region measured and not necessarily the whole skeleton; and how to best integrate information from these newer imaging modalities with biological markers is not clear.
There are more data informing the interpretation of commonly used and widely available biochemical markers (PTH, BSAP, calcium and phosphate) to indicate the predominant underlying bone disease, along with increasing awareness of their limitations. This was particularly highlighted in the discussion regarding the usefulness of bone biopsy to clarify the clinical picture when markers are ambiguous. There are newer markers – both static measurements, such as TRAP‐5b, fibroblast growth factor‐23 (FGF23), α‐Klotho and sclerostin, and functional assays, such as the serum calcification propensity score. How these newer markers will perform in a clinical setting as opposed to a research environment is unknown.
It is now known that both bone mineral density (BMD) measured by dual‐energy X‐ray absorptiometry (DXA) and the trabecular bone score derived from DXA appear independently useful in stratifying fracture risk in patients with and without CKD. Moreover, estimates of bone strength can now be derived from measurements of micro‐architecture, using QCT‐derived finite element analysis. Newer options for stratifying fracture risk include pQCT and HRpQCT. But it is not known whether the addition of pQCT or HRpQCT parameters provides useful information over and above DXA scanning. Nor is it known what to do if advanced CKD patients are stratified to a high‐risk category.
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