1.1 Serum levels of calcium, phosphorus, alkaline phosphatase, total CO2, and PTH—measured by a first-generation immunometric parathyroid hormone assay (1st PTH-IMA)—should be measured in all patients with CKD Stages 2 through 5. The frequency of these measurements should be based on the stage of CKD (Table 2). (OPINION)
1.1.a Patients with known tubulopathies in Stage 1 CKD should have serum phosphorus levels measured at least yearly.
1.2 These measurements should be made more frequently if the patient is receiving concomitant therapy for the abnormalities in the serum levels of calcium, phosphorus, or PTH (Guidelines 4 ,5 ,6 ,7 ,8 ,9, 10), is a transplant recipient (Guideline 17), or is a patient being treated with rhGH (Guideline 11).
1.2.a The target range of serum PTH, in the various stages of CKD, are denoted in Table 3. (OPINION)
A disorder of bone remodeling, the osteodystrophy of CKD, is a common complication. By the time patients require dialysis, nearly all are affected. The onset of the disorder is detectable about the time 50% of kidney function is lost. 8,9 There are multiple histological types of bone pathology in patients with CKD. At the present time, the ability to diagnose the exact type of osteodystrophy of CKD without the pathological description enabled by bone biopsy does not exist. Since high-turnover osteodystrophy can be prevented, 10,11 patients with CKD should be monitored for imbalances in calcium and phosphate homeostasis, and for 2° HPT, by determination of serum calcium, phosphorus, and PTH levels.
Levels of intact PTH determined by immunoradiometric assay (IRMA) or immunochemiluminometric assay (ICMA) are an adequate screening tool to separate high-turnover bone disease (osteitis fibrosa) from low-turnover bone disorders (adynamic bone disorder). 12-17 While the ability to discriminate between the histological types of osteodystrophy of CKD has been demonstrated with determination of blood levels of intact PTH, the optimal target level for PTH in CKD is not known due to limitations in the available data, and the emerging consensus is that those target levels may be lower than currently thought. 18 Recent studies demonstrate that 1st PTH-IMA overestimate the levels of biologically active PTH by detecting C-terminal fragments missing amino acids from the N-terminus of the molecule, which may have an inhibitory activity. Newer 1st PTH-IMA have been developed to overcome this problem by using an antibody that detects the first several amino acids in a two-site assay, but sufficient research has not accumulated to establish the predictive power of these newer assays, and whether they will overcome the shortfalls in the intact hormone assays. Furthermore, the newer assays have not as yet replaced the intact hormone assays as standard clinical tools.
The predictive power of PTH levels is increased by concomitant consideration of alkaline phosphatase levels, 19 although insufficient data exist to determine the sensitivity and specificity of alkaline phosphatase in osteodystrophy of CKD, or its concomitant use with PTH levels. These studies were performed in the era of high prevalence of osteomalacia, and it remains to be determined whether alkaline phosphatase determinations are additive to the newer 2nd generation PTH-IMA. Several other biochemical markers of bone turnover have been developed (osteocalcin, hydroxyproline) and are possibly useful in the evaluation and management of osteoporosis, but CKD affects each of these determinations, and no evidence of their usefulness in this population exists. 19 No bone imaging methods exist for measuring bone disease that can be used diagnostically in place of bone biopsy for osteodystrophy of CKD.
In adults, blood levels of intact PTH begin to rise when GFR falls below 60 mL/min/1.73 m2, and evidence of bone disease due to this 2° HPT may be present at Stage 3 of CKD (Figure 1). Based on data using a less sensitive assay for PTH, it appears that 2° HPT can occur in children in Stage 2 CKD.20 Secondary hyperparathyroidism progresses as kidney function worsens. During this process, changes in blood levels of serum phosphorus (hyperphosphatemia) and calcium (hypocalcemia) occur and contribute to the worsening of hyperparathyroidism and bone disease. Therefore, measurements of serum levels of phosphorus, calcium, and PTH should be made when GFR falls below Stage 2 CKD levels, and these parameters should be monitored thereafter in patients with CKD (Table 2).
Fig 1. Relationship between Serum iPTH Levels and CCR. Values on the y-axis are serum iPTH levels (pg/mL). Values on the x-axis are CCR in mL/min. The lines fitted to the data set are based on 4 different mathematical functions (power, linear, exponential, and logarithmic), rather than on any assumptions about an underlying physiological mechanism. The horizontal line represents the upper limit of the normal range of serum iPTH levels. Reproduced with permission. 21
Most children with CKD or those on maintenance dialysis have some form of osteodystrophy. Despite considerable advances in understanding the pathophysiology, prevention, and treatment of osteodystrophy of CKD, an adequate substitute for bone biopsy in establishing the histological type of osteodystrophy has not been developed. In adults, standard bone radiography can reliably detect bone erosions, but has a sensitivity of approximately 60% and a specificity of 75% for the identification of osteitis fibrosa using such erosions (Figure 2). Skeletal radiography is therefore an inadequate test to diagnose 2° HPT. Sufficient data to assess the sensitivity and specificity of other imaging methods in the diagnosis of osteodystrophy of CKD do not exist. Data on the assessment of the usefulness of quantitative computed tomography in the diagnosis of osteodystrophy of CKD are also insufficient. Standard radiography is more useful in the detection of vascular calcification than it is for osteodystrophy.
Fig 2. Summary ROC Analysis of Erosions on X-Ray as Diagnostic for Osteitis Fibrosa. Summary ROC derived from four individual studies assessing the diagnostic characteristics of erosions on X-ray for diagnosis of osteitis fibrosa. Values on the y-axis are the diagnostic sensitivity and values on the x-axis are the diagnostic specificity. The more effective the test is as a diagnostic, the closer it falls to the upper left hand corner of the graph. The summary ROC curve and its 95% confidence interval provide a summary estimate of the performance of the test based on the meta-analytically combined results from all four studies. The mean threshold point is our best single point estimate of the sensitivity and specificity of erosions on x-ray. In this case, the sensitivity for presence of erosions on x-ray as a tool for diagnosing osteitis fibrosa was 59.8% (95% CI: 44.9-73.2) and specificity was 79.9% (95% CI: 63.2-85.2).
In children and adults, multiple studies have been performed using 1st PTH-IMA to diagnose high-turnover bone disorders and distinguish them from low-turnover disorders. In children with CKD Stage 5, data suggest that PTH levels of approximately 200 pg/mL are useful for distinguishing patients with low-turnover lesions of renal osteodystrophy from those with 2° HPT and high-turnover disease. 22,23 A receiver operating characteristics (ROC) analysis (in essence, a diagnostic meta-analysis) of using 1st PTH-IMA to diagnose high-turnover disorders revealed an estimate of the sensitivity at 93% (95% CI, 87%-97%) and a specificity of 77% (95% CI, 62%-87%), using threshold PTH levels between 150-200 pg/mL. In children, the combination of a serum PTH level >200 pg/mL and a serum calcium value <10 mg/dL was 85% sensitive and 100% specific for identifying patients with high-turnover bone lesions. Serum PTH values <200 pg/mL were 100% sensitive but only 79% specific for patients with adynamic bone.22 Thus, 1st PTH-IMA is a useful test in detecting high-turnover bone disorders (Figure 3).
Fig 3. Summary ROC Analysis of Intact PTH for Diagnosis of High-Turnover Bone Disease. Summary ROC derived from six individual studies assessing the diagnostic characteristics of iPTH levels for the diagnosis of high-turnover bone disease. Values on the y-axis are the diagnostic sensitivity and values on the x-axis are the diagnostic specificity. The more effective the test is as a diagnostic tool, the closer it falls to the upper left hand corner of the graph. The summary ROC curve and 95% CI provide a summary estimate of the performance of the test based on the meta-analytically combined results from all five studies. The mean threshold (indicated in the graph by a diamond icon) is the best point estimate of the sensitivity and specificity of iPTH levels for the diagnosis of high-turnover bone disease.
In adults, studies performed using 1st PTH-IMA to diagnose low-turnover bone disorders use levels of 60 pg/mL as the threshold. In this case, the estimated sensitivity and specificity from the ROC analysis were 70% and 87%, respectively. Thus, 1st PTH-IMA is also useful in diagnosing low bone turnover (Figure 4). Newer assays specific for 1-84 PTH have recently become available and will likely refine and update this information. In the diagnosis and management of osteodystrophy of CKD, the usefulness of these newer assays for PTH is being examined. The normal range for the new assay for 1-84 PTH is 7-36 pg/mL (0.77-3.96 pmol/L), compared to 16-65 pg/mL (1.76-7.15 pmol/L) for 1st PTH-IMA. Thus, the relationship between the two assays is about 1:2 (1-84 PTH to 1st PTH-IMA). The differences in the levels between the two types of assays are a reflection of the levels of circulating PTH fragments that are detected by the 1st PTH-IMA but not by the new 1-84 PTH assay.
Current data are insufficient to assess the diagnostic utility of bone markers such as osteocalcin and serum pyridinoline compounds in the diagnosis of high- versus low-turnover bone disease.
Extensive review of the literature revealed numerous gaps in the available database, necessitating that some aspects of this Guideline be based upon opinion. For instance, there were no data indicating the appropriate frequency with which parameters of osteodystrophy of CKD should be followed.
Four studies in adults and one in children that provided GFR data showed an inverse relationship between serum PTH levels and GFR (Figure 3). The two studies that presented creatinine clearance data in adults showed that serum PTH levels increase as creatinine clearance decreases (Figure 1). A similar finding was seen in children with CKD. It was not possible to find a function that best described the relationship between GFR and PTH levels, or the relationship between serum creatinine or creatinine clearance and PTH levels. Despite this difficulty, these data still permit one to make clinically relevant decisions about when to begin screening for high serum levels of PTH. Based on these studies, it is the opinion of the Work Group that measurements of serum PTH levels in CKD patients should be initiated when CKD Stage 2 is reached.
The most robust available data were related to the use of PTH levels as a marker of osteodystrophy of CKD. In this instance, there were seven studies in adults that met the defined criteria selected for meta-analysis and derivation of an ROC curve. 14,17,24-26 These data demonstrated the usefulness of PTH levels for predicting both high- and low-turnover bone disease (Figure 3 and Figure 4, respectively). Data in children with CKD Stage 5 allow PTH levels also to serve as a predictor of bone turnover based on bone biopsy. 22 The ability of bone imaging methods to substitute for bone biopsy in the diagnosis of osteodystrophy of CKD has only been adequately studied in the case of erosions demonstrated in standard X-rays as a diagnosis of osteitis fibrosa, or in the demonstration of rickets in growing children. A meta-analysis of five studies met the criteria to perform an ROC curve. 14,27-30 The best single-point estimates of the sensitivity and specificity of erosions as a tool to diagnose osteitis fibrosa were 60% sensitivity and 76% specificity. Thus, standard X-rays were not considered an adequate diagnostic tool. There were no adequate studies evaluating the usefulness of quantitative computed tomography (QCT), dual photon absorptiometry, or DXA in the diagnosis of osteodystrophy in CKD patients.
Fig 4. Summary ROC Analysis of Intact PTH for Diagnosis of Low-Turnover Bone Disease. Summary ROC derived from five individual studies assessing the diagnostic characteristics of iPTH levels for the diagnosis of low-turnover bone disease. Values on the y-axis are the diagnostic sensitivity and values on the x-axis are the diagnostic specificity. The more effective the test is as a diagnostic, the closer it falls to the upper left hand corner of the graph. The summary ROC curve and its 95% CI provide a summary estimate of the performance of the test based on the meta-analytically combined results from all five studies. The mean threshold (indicated in the graph by a diamond icon) is the best point estimate of the sensitivity and specificity of iPTH levels for the diagnosis of low-turnover bone disease.
The application of modern techniques for assessing bone turnover from biochemical markers or imaging is severely limited in osteodystrophy of CKD by the effects of CKD on the tests themselves and by the lack of sufficient studies. As a result, accurate diagnosis and management are difficult. The most robust currently available data, using 1st PTH-IMA, permit a general distinction to be made between high- and low-turnover osteodystrophy, but recent studies suggest the need for more accurate assays of PTH levels. Data on PTH and bone disease in CKD Stages 2-4 are missing in children.
These Guidelines promote the use of 1st PTH-IMA in the diagnosis and management of osteodystrophy in patients with CKD. They indicate the limited usefulness of other biochemical markers related—in large part—to lack of information. Inadequate data exist for the utilization of imaging techniques.
Much work is needed to relate biochemical markers of bone turnover to growth and osteodystrophy in CKD. The role of new PTH assays must be further defined. Optimal clinical practice guidelines await outcome studies on the monitoring of osteodystrophy of CKD, and validating outcome data of the recommendations made in these Guidelines.