Striving for Global Excellence in Chronic Kidney Disease Testing

We set out on a mission when we formed the task force on chronic kidney disease (CKD) – a joint project between the IFCC and World Association of Pathology and Laboratory Medicine – to recommend and support the implementation of pathology best practice in CKD testing, globally.

I’m proud to say that we have achieved a lot so far, but it hasn’t been easy.

At the start of this undertaking, we collected information on the current state of national and international activities in the area of pathology testing in CKD. Through consultation with international specialist organizations, such as Kidney Disease Improving Global Outcomes (KDIGO), we assessed current best practice and recommended guidelines and policies.

I admit that one of our biggest tasks is one of communication. Volunteers amongst the medical specialists, primary care physicians and clinical laboratory specialists involved do all the work necessary on top of their normal health service delivery workloads. So, efficient and effective communication is crucial to engage all stakeholders in the process. It’s not easy and there are no well-documented strategies in place. The knowledge that we share and gain is largely region- or country-specific, so it’s a challenge working with cross-boundary differences. The idea behind our best practice recommendations – when adopted as policy by renal specialists and clinical labs – is to facilitate the effective communication between renal medical specialists and primary care physicians by way of the clinical laboratory report.

What have we achieved so far? Our recommendations of pathology best practice for CKD have been adopted internationally. The traceability of creatinine assays to recognized international reference materials using reference measurement procedures have been adopted by the major in vitro diagnostic equipment and reagent providers. But with approximately 100 companies now providing reagents and instruments for creatinine measurements, considerable work is still needed. Professional organizations, such as KDIGO and IFCC, as well as clinical lab workers must inform these companies of the importance of establishing traceability to recognized international reference standards for their clinical CKD assays.

We’ve also achieved the worldwide recommendation of estimated glomerular filtration rate reporting based on creatinine measurements, using traceable assays and the best available equation. Adoption is widespread in regions across North America, Europe, Australasia and Asia-Pacific.

We’re now working hard to extend these concepts to remaining global regions. Major obstacles will continue to be the effective communication between all stakeholders, and the adoption of appropriately traceable assays within clinical laboratories. We’ve come a long way so far, and we will continue working until we’ve achieved our overall aims.

Howard Morris is a professor of medical sciences at the University of South Australia, vice president of the IFCC and chair of the IFCC-International Osteoporosis Foundation Working Group on standardization of bone marker assays.

How Clinically Useful Are Bone Turnover Markers?

Metabolic bone disease is highly prevalent, and although bone turnover marker (BTM) assays have a key role to play in its diagnosis and monitoring, the lack of internationally recognized guidelines for the interpretation of patient results has limited their clinical usefulness.

Patients with osteoporosis, in particular postmenopausal osteoporosis, make up the largest group of BTM assay recipients, where it is used to assess fracture risk and/or to guide therapy and monitor response.

We set up a task force, in collaboration with the International Osteoporosis Foundation, to identify a consensus reference standard BTM. Although we believe in its clinical usefulness, a thorough review of current reports has indicated that there are insufficient data to guide the use of any particular BTM for clinical use, despite the availability of a body of evidence to suggest that they may be useful. For example, of 22 studies that reported on the relationship between a BTM and future risk of fracture, 18 linked elevated BTM level with fracture risk (1). However, the problem is that a number of BTM assays have been used in these studies, so no apparent benefit has been found for any one particular BTM as a bone formation or a bone resorption marker.

Based on our own research of these reports, we agreed that serum beta-CrossLaps (β-CTx) appeared to be a suitable bone resorption marker, and procollagen type 1 amino-terminal propeptide (PINP) was a suitable bone formation marker.

A second working group from the North American National Bone Health Alliance also conducted a review and reached the same conclusions.

We’re now in a position to investigate this further, but we do have some concerns: we are currently investigating whether or not current commercial clinical assays for serum β-CTx and serum PINP provide comparable results. Once we are satisfied that all assays are producing comparable results, we can confidently conduct metaanalyses of clinical trial data where these assays have been used and combine data from all assays used by clinical laboratories.

Our plan is to calculate the discrepancies in measurements for these BTMs across different manufacturers, reagent lot numbers and laboratories. Our goal is to establish the least significant change for each BTM that will allow clinicians to confidently analyze data irrespective of the clinical lab or assay used.

Right now, I admit that it’s not guaranteed that our recommendations will be incorporated into clinical guidelines. A major immediate task is to reduce variation between BTM levels so that only variation in bone turnover is being assessed. If we achieve this first and foremost, the clinical use of BTMs for fracture prognosis can be optimized. However, there is still a lot about the basic physiology of BTMs that is not understood; for example, we know that levels of some BTMs are markedly affected by eating. Initially, this was attributed to calcium consumption, based on the rationale that calcium affected calciotropic hormones and, therefore, indirectly affected bone turnover (2). But more recently, it’s been suggested that gut hormones, such GLP-1, markedly affect serum β-CTx levels (3), while another BTM, osteocalcin, might actually be a hormone that regulates whole energy metabolism of the body (4). If whole energy metabolism is related to BTMs, there will be a great deal of variation between individuals independent of their bone status.

Irrespective of ongoing research, we will not be able to proceed further unless we successfully conduct the studies and harmonization of the assays as planned.