or Bone Histology: Are We Still Waiting for a Verdict From the CKD-MBD Grand Jury?

or Bone Histology: Are We Still Waiting for a Verdict From the CKD-MBD Grand Jury?

Editorial PTH and/or Bone Histology: Are We Still Waiting for a Verdict From the CKD-MBD Grand Jury? Related Article, p. 559 C hronic kidney disease...

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Editorial PTH and/or Bone Histology: Are We Still Waiting for a Verdict From the CKD-MBD Grand Jury? Related Article, p. 559


hronic kidney disease–mineral and bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism encompassing one or more of the following conditions: aberrations in calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism; abnormalities in bone mineralization, volume linear growth, strength, and turnover; and extraskeletal calcification. The disorder is associated with increased mortality1 and fracture risk.2,3 In essence, bone turnover may be understood as the ratio between bone formation and bone resorption. In clinical practice, patients with CKD exhibit bone formation rates along a spectrum ranging from abnormally low to very high. The gold standard for the diagnosis and classification of bone disorders is transiliac crest bone biopsy. In this procedure, tetracycline labeling is used to quantify parameters linked to bone turnover rate, including eroded surfaces, fibrosis, number of osteoclasts, and woven bone. In routine clinical practice, bone biopsy is not frequently used because it is costly, invasive, and often painful. Clearly, a noninvasive method of evaluating bone disease is required to identify abnormalities in bone structure, mineralization, and remodeling; predict clinical outcomes; and guide treatment decisions. In this search for the Holy Grail, several bone biomarkers (single or in combination) have been studied for both the diagnosis and monitoring of bone turnover. However, all have limitations in the assessment of renal bone disease. The first biomarker used for biochemical assessment of bone turnover was PTH.4 Most studies conducted in the 1980s and early 1990s demonstrated a relatively good correlation between levels of PTH and bone histomorphometric parameters.5 However, nearly all these studies used a now-unavailable firstgeneration immunoradiometric assay (Allegro PTH assay; Nichols Institute Diagnostics). For patients receiving dialysis, the 2003 NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) guideline6 recommends a PTH target of 150 to 300 pg/mL, a range apparently associated with normal bone turnover. However, this recommendation is based on the sensitivity and specificity of the Allegro PTH assay. Moreover, studies conducted in the last 12 years have demonstrated poor correlation between PTH levels and bone turnover (Table 17-18). Additional biomarkers, most often total or bonespecific alkaline phosphatase (bALP) or amino-terminal Am J Kidney Dis. 2016;67(4):535-538

propeptide of type 1 procollagen (P1NP; a bone formation marker), have been evaluated in relation to bone turnover, but the studies were small and inconclusive. In a cohort of patients receiving long-term hemodialysis, GalMoscovici et al14 described a close correlation (r 5 0.84; P , 0.05) between PTH level , 150 pg/dL and lowturnover bone disease. Subsequently, Barreto et al16 used bone histomorphometry to show that two-thirds of dialysis patients with intact PTH (iPTH) levels of 150 to 300 pg/mL had low-turnover bone disease and onequarter had high-turnover bone disease. This discrepancy between apparently normal iPTH levels and pathologic bone biopsy findings was similar at the 1-year follow-up. In the largest study of bone biopsy in patients with CKD, Malluche et al17 showed that low turnover is a frequent finding in dialysis patients, especially white patients. The authors found that PTH level was not a significant predictor of bone turnover in black dialysis patients, an observation possibly related to PTH resistance. In contrast, PTH concentration was a predictor of low bone turnover in white patients receiving dialysis. Table 1 contains a summary of studies that have examined the specificity and sensitivity of PTH and bALP levels. PTH and bALP levels have only moderate discriminative power and prediction of bone turnover status; importantly, the combination of the 2 biomarkers does not improve sensitivity or specificity. In this issue of AJKD, Sprague et al19 report the second largest bone biopsy study evaluating the usefulness of circulating biomarkers for predicting bone histopathology. In a cross-sectional retrospective diagnostic test study, the authors determined the predictive value of levels of serum PTH (both intact and whole), bALP, P1NP, and other markers of bone turnover in 492 patients treated with dialysis. In predicting low bone turnover, areas under the curve for iPTH and bALP were 0.701 and 0.757, respectively. The corresponding areas under the curve to predict high turnover were 0.724 for iPTH and 0.711 for bALP. The combination of PTH and bALP levels offered minimal additional discrimination, and P1NP level did not improve diagnostic accuracy. In conclusion, even if both iPTH and bALP levels Address correspondence to Luminita Voroneanu, MD, Nephrology Department, Dialysis and Renal Transplant Center, “C.I. Parhon” University Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, No. 50 Carol I Blvd, Iasi, Romania. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.11.028 535

Covic, Voroneanu, and Apetrii Table 1. Relationship Between Bone Biopsy and Bone Biomarkers Study

Study Population

Fletcher7 (1997)

73 dialysis patients

Monier-Faugere8 (2001)

51 dialysis patients

Coen9 (2002)

35 HD patients

Coen10 (2002)

79 NDD-CKD patients; 107 HD patients

Sawaya11 (2003)

76 ESRD patients

Bervoets12 (2003)

84 CKD3-5 patients

Lehmann13 (2005)

132 CKD3-5 patients

Gal-Moscovici14 (2005)

96 dialysis patients

Lehmann15 (2008)

132 CKD3-5 patients

Barreto16 (2008)

97 dialysis patients

Malluche17 (2011)

630 dialysis patients

Haarhaus18 (2015)

40 dialysis patients


For high bone turnover: iPTH . 100 pg/mL has sensitivity of 81%, specificity of 66% Ratio of PTH(1-84) to carboxy-terminal PTH fragments predicts bone turnover with acceptable precision for biological measurements Ratio of PTH(1-84) to PTH(7-84) is not marker of low turnover and is of no use in noninvasive histologic diagnosis Slopes of correlations of iPTH vs bone formation rate, osteoblast surface/bone surface, and osteoclast surface/bone surface were significantly steeper in dialysis vs NDD-CKD patients iPTH levels correlate with bone turnover in white but not African American patients Predictors of low turnover: PTH , 237 pg/mL has sensitivity of 78%, PPV of 47%; bALP has a sensitivity of 83%, PPV of 57% For low vs high turnover in CKD3-4: AUCs of 0.94 for biPTH, 0.91 for iPTH; for low vs high turnover in CKD5: AUCs of 0.86 for biPTH, 0.85 for iPTH In analyses including all patients, no correlation between PTH and bone turnover; in the PTH , 150 pg/mL subgroup, there was a correlation with low bone turnover For high vs low/normal bone turnover: PTH . 161 pg/mL has sensitivity of 75%, PPV of 89% For low turnover: iPTH , 150 pg/mL has sensitivity of 50%, specificity of 85%, PPV of 83% For high turnover: iPTH . 300 pg/mL has sensitivity of 69%, specificity of 75%, PPV of 62% PTH level is a predictor of high bone turnover in both black and white patients and of low bone turnover in white (P , 0.001) but not black patients PTH, bALP, and B1x have similar diagnostic accuracy in distinguishing low from nonlow bone turnover

Abbreviations: AUC, area under the curve; B1x, an isoform of bALP; bALP, bone alkaline phosphatase; biPTH, biointact PTH; HD, hemodialysis; CKD, chronic kidney disease; ESRD, end-stage renal disease; iPTH, intact parathyroid hormone; NDD-CKD, non– dialysis-dependent chronic kidney disease; NPV, negative predictive value; PPV, positive predictive value; PTH(1-84), full-length PTH (ie, contains amino acids 1-84); PTH(7-84), amino-terminally truncated PTH (ie, missing the first 6 amino acids).

provide only suboptimal acceptable discriminating ability for bone turnover, iPTH level continues to be the best-available tool to discriminate bone turnover. Currently, the KDIGO (Kidney Disease: Improving Global Outcomes) guideline20 (2009) and ERBP (European Renal Best Practice) commentary statement21 (2010) suggest that serum PTH or bALP measurements can be used to assess bone disease because very high or low values are predictive of bone turnover. However, although the extremes of PTH concentration range are correlated with bone turnover, in essence, PTH levels reflect parathyroid activity much more so than underlying bone remodeling.22,23 When PTH levels are in the KDIGOrecommended range, that is, 2 to 9 times the upper limit of normal, a 1-time measurement reveals minimal predictive information regarding bone histology.23 In the study by Sprague et al, the utility of PTH level in differentiating high from nonhigh bone turnover using the KDIGO-recommended cutoff had relatively high specificity but low sensitivity (using iPTH , 2 times the upper limit of normal to detect low turnover had a specificity of 65.3% and a sensitivity of 65.7%, whereas using iPTH . 9 times the 536

upper limit of normal to detect high turnover had a specificity of 85.8% and a sensitivity of 37.0%). Although recommended by current guidelines, PTH measurements have not proved to be specific or sensitive enough to accurately diagnose bone turnover in all patients. The reasons for this weak correlation are not clear, but may include differences in PTH assays, therapies, and the racial composition of study populations. Secular changes in the dialysis population (with more diabetic and elderly patients in recent times) may also affect the strength of the correlation. With respect to PTH assay differences, there have been 3 main developments over time: first generation (uses a single antibody directed toward the carboxyterminal part of the peptide; lacks specificity), second generation (uses a pair of antibodies, one against an epitope within amino acids 39-84 and the other to an epitope within amino acids 13-34; measures socalled “iPTH” and other fragments that accumulate when kidney function declines), and third generation (uses an anti–carboxy-terminal antibody similar to that of the second-generation assays, plus an anti– amino-terminal antibody directed against an epitope found within the first 12 amino acids of PTH).24 Am J Kidney Dis. 2016;67(4):535-538


Unfortunately, not one of these assays is perfect and the results they give can differ to an extent that is clinically relevant. Intermethod variability may be explained in part by antibody specificity and standardization problems. Furthermore, results can differ depending on the temperature and speed of sample processing, and it appears that the stability of PTH in serum is greater when blood samples are collected in EDTA tubes versus those lacking preservative.25 The short half-life of the whole active hormone (approximately 2-4 minutes) could generate significant intraindividual variation that may increase by 25% in patients receiving dialysis.26 In this context, KDIGO guidelines recommended following trends rather than individual values. Due to controversies related to the variability of different assays for PTH, Sprague et al decided to analyze both iPTH and whole PTH in order to minimize the potential bias from inactive fragments of PTH (which are often seen in patients with CKD and are detected by iPTH assays).19 Unfortunately, only one value for each patient was determined. Trending changes in PTH, an issue that has not been assessed by Sprague et al or other studies, may improve diagnostic precision and provide better clinical guidance, as suggested by KDIGO. In addition, there are several other limitations of the Sprague et al study. The use of samples originating from only 4 countries and the low prevalence of patients with diabetes may limit the study’s generalizability. There were no data for ethnic and racial groups, and though it is unlikely, based on the geographical source of the samples, that the Sprague et al cohort included many African Americans, it has been demonstrated by several studies that compared with white patients that African Americans have greater bone volumes, higher PTH levels, less hyperphosphatemia, and lower serum calcium, 25hydroxyvitamin D, and fibroblast growth factor 23 (FGF-23) levels. Furthermore, it is unclear if the cohort studied by Sprague et al is representative of current patient populations and treatment paradigms given that the biopsy specimens were obtained between 1993 and 2007 and the patients were treated predominantly with calcium-based phosphate binders. There also was no analysis of parameters of cortical bone, which appears to be preferentially lost in patients with CKD and hyperparathyroidism. Furthermore, the diagnostic performance of other newer diagnostic biomarkers such as FGF-23, sclerostin, or TRAP5b could not be determined because serum samples were of limited quantity. Despite its weaknesses as a biomarker, PTH represents perhaps the best current option for noninvasive assessment of bone turnover. The study by Sprague et al further supports this conclusion, Am J Kidney Dis. 2016;67(4):535-538

providing evidence that measuring PTH could be useful in clinical practice as a tool to evaluate bone turnover. Although extreme values of PTH are undeniably linked with bone turnover, most values will fall in a zone where biological and analytical inconsistency will require careful interpretation. In this context, other potential biomarkers of bone turnover and structure should be studied for a better and clearer description of bone structure. Thus, subsequent prospective studies are required to further define clinically useful markers in the assessment of bone lesions in CKD-MBD. Adrian Covic, MD, PhD Luminita Voroneanu, MD Mugurel Apetrii, MD Gr. T. Popa University of Medicine and Pharmacy Iasi, Romania

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Covic is a consultant for Fresenius Nephrocare. Drs Voroneanu and Apertrii report that they have no relevant financial interests. Peer Review: Evaluated by a Co-Editor and the Editor-in-Chief.

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Am J Kidney Dis. 2016;67(4):535-538