Parathyroid Hormone, Alkaline Phosphatase and Fibroblast Growth Factor 23
Orlando M. Gutiérrez, MD
The management of chronic kidney disease-mineral bone disorder (CKD-MBD) is central to the care of patients with kidney disease. Key to these efforts is the availability of clinically accessible biomarkers that can help distinguish between a wide variety of bone and mineral disturbances related to kidney failure. Two such markers, parathyroid hormone (PTH) and alkaline phosphatase, are already well-established in current guidelines for managing CKD-MBD and are familiar to most clinical practitioners.
Despite their familiarity, however, there remains considerable uncertainty regarding the optimal use of these biomarkers to guide therapy, particularly with respect to the levels of PTH that should be targeted in each stage of CKD. With the recent discovery of fibroblast growth factor 23 (FGF-23)—a bone-derived hormone that regulates phosphorus and vitamin D metabolism—a novel biomarker has emerged that may ultimately help to clarify some of this uncertainty, especially in regard to the management of disordered phosphorus metabolism in CKD. In this review, the benefits and potential pitfalls of measuring PTH and alkaline phosphatase, and how FGF-23 may eventually fit into the management of CKD-MBD, will be discussed.
PTH has been a mainstay in the evaluation of bone and mineral metabolism in CKD patients for more than three decades. The long-term consequences associated with persistently elevated PTH levels in CKD have been well-described and include high-turnover bone disease, anemia, cardiovascular disease (CVD), and mortality.1 As a result, both the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend that PTH levels should be regularly monitored beginning in stage 3 CKD (i.e., estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m2), and that elevated levels should be treated with a combination of dietary phosphorus restriction and therapy with vitamin D and/or calcimimetics.1,2 Unfortunately, however, despite the conformity of these guidelines with respect to the importance of monitoring and treating elevated PTH levels, no clear consensus has arisen as to the ideal target ranges of PTH in each stage of CKD.
There are several reasons for this uncertainty. First, intact PTH levels have been shown to have rather disappointing sensitivity and specificity for predicting underlying bone histology in CKD patients, particularly when using the newer second-generation intact PTH assays. This is largely because these assays detect not only the full-length active peptide but also various C-terminal fragments, which can result in substantial variation in PTH measurements depending on the type and number of circulating fragments in collected blood samples.3,4 In addition, natural diurnal variation in PTH and differences in specimen collection and processing can also increase variability in PTH measurements, further limiting the clinical utility of single PTH measures for predicting bone histomorphometry.2,5,6 In recognition of these concerns, the most recent guidelines from the KDIGO work group did not advocate specific PTH cut-off levels for each CKD stage, but instead emphasized the importance of following PTH trends over time (provided that the intact PTH assay used remains consistent), and suggested that PTH levels should be kept within two to nine times the upper level of normal for the specific PTH assay used (essentially a range of 130 to 600 pg/mL, depending on the commercial assay).2 This broad range reflects the methodological difficulties in measuring PTH levels in CKD patients, and underscores the challenge in trying to develop one set of guidelines that can be uniformly applied across the spectrum of clinical practice.
Further complicating the task of coming up with one set of guidelines is the possibility that PTH levels considered optimal for bone health may not be optimal for non-skeletal outcomes, such as CVD events and mortality. For example, although KDOQI recommends that PTH levels be maintained between 150-300 pg/mL for patients with stage 5 or 5D CKD,1 a recent analysis of 748 patients undergoing maintenance hemodialysis showed that PTH levels between 100 and 150 pg/mL were associated with the best five-year survival after accounting for surrogate markers of malnutrition and inflammation complex.7 Similar results were reported in a Japanese study of 27,404 hemodialysis patients in which PTH levels below 120 pg/mL were associated with the lowest mortality.8 Furthermore, in a study of 515 male U.S. veterans with non-dialysis dependent CKD (for whom KDOQI recommends PTH levels of 70-110 pg/mL), PTH levels of 65 pg/mL or less versus more than 65 pg/mL were associated with significantly lower mortality rates.9 While these data suggest that PTH levels lower than those currently recommended by KDOQI may be associated with better long-term survival, it is important to note that other studies have reported a U-shaped relationship between PTH and survival, with the risk of death markedly increasing in the lower tail of the PTH distribution.10,11 In addition, the lack of standardization of PTH assays in these studies makes it difficult to extrapolate the results from one study to another, or to everyday clinical practice. Nevertheless, in the aggregate, these data suggest that PTH ranges considered optimal for bone health may not be the same as those for survival outcomes in CKD.
Despite these uncertainties, given the robust association between elevated PTH levels with adverse cardiovascular and survival outcomes,1 and prior data showing a clear benefit of lowering PTH levels for the treatment of high-turnover bone disease,12-14 treatment of elevated PTH levels will likely remain a staple of CKD-MBD management for the foreseeable future. However, until a consensus is reached with respect to the ideal ranges of PTH for each stage of CKD, uncertainty as to which levels to target will remain prominent, leaving it largely to the discretion of individual practitioners. This may ultimately result in gradual increases in average PTH levels among U.S. hemodialysis patients over time, especially as pending bundling legislation threatens to curtail reimbursement of PTH-targeted medications, such as activated vitamin D analogs. If so, close surveillance of national outcomes data will need to be performed to ensure that clinical outcomes do not suffer as a consequence, keeping in mind the importance of considering both skeletal and non-skeletal outcomes.
Alkaline phosphatase is an enzyme that removes phosphate from proteins and nucleotides and can be detected in a variety of tissues throughout the body.15 Because the highest concentrations of the enzyme are found in the liver and bone, an elevated total alkaline phosphatase level is most often indicative of either liver disease (usually in conjunction with elevated levels of other liver-specific analytes) or bone pathology, such as high-turnover bone disease. While the measurement of bone-specific alkaline phosphatase can help to differentiate between these possibilities, to date this assay is not widely available in clinical settings.
The measurement of alkaline phosphatase has been advocated as an adjunct test for non-invasively assessing bone turnover in CKD patients, particularly in clinical scenarios in which elevated PTH levels may be challenging to interpret.2 These recommendations were based upon studies that showed that elevated bone alkaline phosphatase levels have some predictive value in diagnosing high-turnover bone disease in both pre-dialysis and end-stage kidney disease populations.2,16-18 As such, although the KDOQI guidelines do not address alkaline phosphatase in the management of CKD-MBD, the more recent KDIGO guidelines recommend that the measurement of alkaline phosphatase levels should commence in stage 3 CKD, and that in patients with stage 4 -5 CKD, alkaline phosphatase should be measured at least every 12 months, and more frequently when monitoring response to therapy.2 Unfortunately, there are very little data as to whether using alkaline phosphatase to guide therapy actually improves hard clinical outcomes, such as fracture rates. More research is needed to determine whether incorporating alkaline phosphatase levels into standard diagnostic and treatment algorithms can substantively improve skeletal outcomes in CKD.
In addition to its potential utility in assessing bone health, recent evidence suggests that alkaline phosphatase levels may have some value for predicting CVD outcomes. Large prospective studies showed that elevated alkaline phosphatase levels were independently associated with increased risks of CVD-related hospitalization and mortality in patients across the spectrum of kidney function.19-21 Although the mechanisms for these associations were unclear, it is possible that a higher alkaline phosphatase level may be linked with vascular calcification—itself a strong risk factor for adverse outcomes—either directly via the hydrolysis of known inhibitors of vascular calcification,15 or indirectly as a surrogate marker for other mediators of vascular calcification such a phosphate retention or abnormal vitamin D metabolism. While intriguing, whether the addition of alkaline phosphatase to standard biochemical measurements can meaningfully improve cardiovascular risk stratification in CKD patients is unknown. Therefore, until such data become available, there seems little reason to advocate the measurement of alkaline phosphatase beyond as an adjunct test for assessing bone turnover in CKD patients when the interpretation of elevated PTH levels is otherwise unclear.