Does PTH Offer Additive Value to ALP Measurement in Assessing CKD-MBD?

Bony abnormalities are common amongst patients with chronic kidney disease (CKD), especially in those requiring dialysis (1). Originally termed renal osteodystrophy, this disorder has been expanded in recent years to include extraskeletal “soft-tissue” calcification and abnormalities of biochemical surrogates, and is now called chronic kidney disease-mineral bone disorder (CKD-MBD) (2). Historically, 4 types of CKDassociated bone disease were described: osteitis fibrosa cystica, low turnover or adynamic bone disease, mixed uremic osteodystrophy (MUO), and osteomalacia (1). The gold standard for diagnosis of the bone component of CKD–MBD is biopsy-based histological analysis, but this procedure is rarely performed in clinical practice. Management of CKD-MBD is based largely on surrogate laboratory markers, in particular parathyroid hormone (PTH). Hyperparathyroidism is typically associated with the development of osteitis fibrosa, traditionally considered the major form of CKD-MBD. This may manifest clinically as bone pain, and is reflected in an increased incidence of hip fracture amongst dialysis patients, with fracture occurring at a younger age than in the general population (3,4). More recently, there appears to have been a shift in the phenotype of CKD-MBD, with adynamic bone disease becoming more prevalent (5). It has been suggested that this is the result of an ageing dialysis population with increasing diabetes prevalence, in addition to increased calcium loading (6). Prior to the 1980s, laboratory evaluation of renal osteodystrophy centered on measurement of calcium and phosphate in conjunction with alkaline phosphatase (ALP), an enzyme found within the osteoblasts (amongst other locations) and which demonstrates increased plasma activity in situations of high bone turnover. Alkaline phosphatase has limitations as a marker of renal bone disease because it exists in several isoforms, most of which are unrelated to bone turnover. Approximately 45% of circulating ALP reflects the bone isoform with a similar fraction being derived from the liver: in the presence of concomitant liver disease, plasma ALP activity may be increased irrespective of bone turnover. The role of PTH in driving increased bone turnover has long been appreciated but measurement of PTH was initially hindered in renal patients by non-specificity of available radioimmunoassays which detected retained biologically inactive C-terminal fragments of the hormone (6). In the late 1980s more specific PTH assays appeared, based on dual antibody recognition and claiming specificity for the biologically active hormone (7, 8). With increasing automation, these assays became widely available and remain the bed-rock of CKD-MBD management. Near universal increases of plasma PTH concentrations are seen in patients with kidney failure who haven’t received dialysis (9). Guidelines for CKD-MBD management currently recommend regular measurement of ALP and PTH (2). Recommendations for patients receiving dialysis are to target PTH concentrations 2 – 9 times the upper limit of the reference range (for the assay in use) and to make therapeutic decisions based on trends rather than single values (2). Serum total ALP is seen as an adjunct to PTH measurement with no clearly defined management targets. For many reasons the use of PTH concentration in CKD-MBD monitoring should be questioned. Claimed specificity of the original 2-site PTH assays appears to have been a false dawn, with reported detection of accumulated inactive, or non-classically active, C-terminal forms of PTH (e.g. PTH7-84), which may represent 50% of total PTH in dialysis patients (10,11). Recently, the formation of oxidized, biologically inactivated, but immunologically reactive, PTH has been demonstrated to be increased in patients with kidney failure (12,13). The extent of oxidation varies between individuals but is significant, such that the majority of PTH detectable by immunoassay in hemodialysis patients may be inactivated. Technical issues with the assays persist, COMMENTARIES