266
El-Husseini and Sawaya
What is the Role of Bone Biopsy in the Management of Adult Dialysis Patients? Amr El-Husseini and Boutros Peter Sawaya Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky
Definitions and Classifications In 2005, Kidney Disease: Improving Global Outcomes (KDIGO) sponsored a conference entitled “Definition, Evaluation and Classification of Renal Osteodystrophy.” The results of this conference were published in 2006 (1). KDIGO introduced the term chronic kidney disease-mineral and bone disorder (CKD–MBD) and defined it as a “systemic disorder of mineral and bone metabolism due to CKD.” The traditional definition of renal osteodystrophy (ROD) did not accurately represent the diverse clinical spectrum of CKD–MBD. KDIGO guidelines recommended that the term “renal osteodystrophy” be restricted to describing the bone pathology associated with CKD that usually requires a bone biopsy for precise diagnosis. Based on studies that included histomorphometric analysis, an expanded classification system was developed at the consensus conference that took into account three distinctive parameters, the so-called TMV classification: turnover (T), measured by assessing bone-formation rate or activation frequency; mineralization (M), assessed by measuring unmineralized osteoid thickness and mineralization lag time; and bone volume (V). The TMV classification has expanded on the previously described histomorphometric abnormalities that included hyperparathyroid bone disease, adynamic bone disease, osteomalacia, and a mixture of an abnormal bone turnover and a defective mineralization (mixed uremic osteodystrophy) (2–6). Lack of Specificity in Bone Biomarkers and Other Noninvasive Tools Measurement of circulating parathyroid hormone (PTH) may not provide enough diagnostic information on the type of bone turnover, except perhaps
Address correspondence to: Peter Sawaya, MD, University of Kentucky, Division of Nephrology, Bone and Mineral Metabolism, 800 Rose St, MN 672, Lexington, KY 40536, Tel.: 859-323 2635, Fax: 859-257 3927, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 266–269 DOI: 10.1111/sdi.12236 © 2014 Wiley Periodicals, Inc.
for patients with extreme levels. It is beyond the scope of this brief communication to discuss in details the multiple reasons why there is a disconnection between PTH serum levels and bone turnover. But it is abundantly evident that bone turnover is affected by many other circulating as well as local factors (7,8). Furthermore, skeletal resistance to PTH and a remarkable variability in PTH assay hinder its prediction of the underlying bone turnover (9,10). Additionally, total alkaline phosphatase (ALP) and bone-specific ALP do not add much to the utility of PTH in predicting the underlying bone pathology (11). Other bone-derived turnover biomarkers are even less useful in dialysis patients since they tend to accumulate when renal function is decreased. In fact, KDIGO guidelines do not recommend the routine measurement of these biomarkers in CKD 3–5D (11). In contrast to the general population, the ability to predict fracture risk by measuring bone mineral density (BMD) in patients with CKD stages 3–5 is not yet confirmed (12). Moreover, BMD cannot distinguish between different types of renal osteodystrophy. Postmenopausal or age-related osteoporosis can be detected by BMD only at the earliest stages of CKD. In later stages and in the presence of CKD-MBD, the underlying decreased bone volume is better defined in the context of renal osteodystrophy and not osteoporosis (12). Femoral dual energy X-ray absorptiometry (DEXA) is a good noninvasive measure of cortical bone volume, but DEXA of the spine does not give reliable information on cancellous bone volume (13). Current evidence does not support a role for imaging in the diagnosis of renal bone disease in patients with CKD (14). Based on a systematic review of studies spanning over 20 years, abnormalities in bone mineralization are present in approximately 40% of adult patients on dialysis (11). In a more recent study, a mineralization defect was found in only 3% of 630 patients (15). The exact clinical implications of these abnormalities remain to be established. But older studies suggested potential association of mineralization defects with bone pain and fracture (16,17). It is interesting to observe that, at least in children, mineralization defects may persist despite suppression of secondary hyperparathyroidism with active vitamin D therapy (18).
267
BONE BIOPSY IN THE MANAGEMENT OF ADULT DIALYSIS PATIENTS
TABLE 1. Modified KDIGO proposed indications for bone biopsy in dialysis patients with rational and action plan Indication 1-Unexplained fractures and bone pain
Rational A-Identify precisely the degree of bone turnover
B-Assess bone volume
C-Assess for mineralization defects
D-Rule out micro-fractures E-Rule out aluminum deposition F-Diagnose unsuspected conditions: multiple myeloma, lymphoma, sarcoidosis, infection, etc. 2-Unexplained hypercalcemia
A- Possible HBT with moderate elevation of PTH B- Possible LBT with moderate elevation of PTH, with or without aluminum C- Diagnose unsuspected conditions (see 1F)
Action plan 1a-If high bone turnover (HBT), suppress PTH medically or surgically as deemed necessary. 1b-If low bone turnover (LBT), avoid active vitamin D therapy and calcium-containing phosphate binders, attempt aggressive control of serum phosphorus, consider lower calcium bath, encourage judicious weight-bearing exercises as tolerated and, when pertinent, be persistent in counseling for smoking cessation. 1c-If bone volume is very low with evidence of excessive resorption out of proportion to the degree of hyperparathyroid bone disease, then a search for potential causes (i.,e., underlying malignancy) is warranted and the use of anti-resorptive therapy that is appropriate for dialysis patient may be deemed necessary. 1d-If osteomalacia is present, a thorough search for possible causes is indicated (i.e., vitamin D deficiency, aluminum or fluorides accumulation, chronic hypophosphatemia, etc.) Treatment of underlying cause, including vitamin D therapy as appropriate. 1e-Treatment of the underlying cause (see 1a-1d &1f) 1f-Identify the source and institute chelation therapy 1g-Treatment of the underlying pathology
See 1a and 1c See 1b and 1f See 1c and 1g
3- Unexplained and persistent hypophosphatemia
A- Assess for mineralization defects
See 1d
4- Unexplained and persistent hyperphosphatemiaa (i.e., without evidence of noncompliance or severe hyperparathyroidism)
A- Possible HBT with moderate elevation of PTH. B- Possible LBT with moderate elevation of PTH
See 1a
5- Patients with divergent PTH and ALP results
A- Elevated ALP out of proportion to PTH: rule out underlying severe HPT or osteomalacia B- Moderate elevation in PTH with low AP: rule out LBT
See 1b See 1a, 1d and 1f
See 1b
6- Suspicion for osteomalacia
A- Presence of risk factors, symptoms, or elevated ALP
See 1d
7- Suspicion for aluminum-associated bone disease
A- History of exposure to aluminum, bone pain, muscle weakness, erythropoietinresistant microcytic anemia, hypercalcemia, neurological symptoms, elevated serum aluminum levels or positive deferoxamine test
See 1f
8- Prior to bisphosphonate therapy
A- Rule out LBT with absolute certainty as their use would be contraindicated.
See 1b
9- Prior to parathyroidectomya if the diagnosis is not clear or there is suspicion of underlying aluminum accumulation
A- Parathyroidectomy precipitously worsens aluminum bone disease.
See 1f
a
Not included in KDIGO guidelines.
268
El-Husseini and Sawaya
Limitations of Bone Biopsy in Clinical Practice While undoubtedly bone biopsy with histomorphometric analysis is the gold standard for defining bone abnormalities in dialysis patients, it is still a mere “snap shot” of a continuous and dynamic disease. Patients may go through phases with different abnormalities, or the initial changes may progress over time with various therapies and dialysis prescriptions. Repeated bone biopsies are certainly not practical or even acceptable as a valid “monitoring” tool. In addition, the technique of bone biopsy is not a required procedure for nephrologists to master nor it is in the curriculum of an interventional nephrology program. Finally, the number of centers with capability of performing comprehensive histomorphometric analysis on decalcified bone is limited. However, perhaps of all organ tissue subjected to analysis, bone is the most readily preserved and transported (19). Practical Indications for Bone Biopsy in Adult Dialysis Patients Bone biopsy is a minimally invasive procedure, but it is usually limited to certain settings where precise diagnosis may dictate a specific therapy or action plan (19). These indications are observed in relatively few patients and typically reflect extreme changes in bone pathology, as it is unrealistic to routinely collect bone biopsies from patients with CKD-MBD. In 2003 (and in this journal), we discussed potential indications for bone biopsy in end-stage renal disease patients (19). Very similar indications were put forth by the KDIGO guidelines in 2006 and updated in 2009 (1,11). The premise of the bone biopsy is that it is the most accurate tool for the diagnosis of renal osteodystrophy providing definitive TMV classification (11). While one cannot be dogmatic about these indications, they do provide a practical framework for clinicians to apply during their assessment of dialysis patients. KDIGO guidelines suggest that it is reasonable to perform a bone biopsy in the following various settings including, but not limited to: unexplained fractures, persistent bone pain, unexplained hypercalcemia, unexplained hypophosphatemia, possible aluminum toxicity, and prior to therapy with bisphosphonates in patients with CKD–MBD. These recommendations were not graded (11). In Table 1, we list modified KDIGO indications for bone biopsy and expand on the pathophysiologic rational behind performing the biopsy and how the results may direct further specific therapy or action plan. Future Directions and Conclusion In the future, bone biopsy may further assist in the management of dialysis patients by assessing
bone fragility. Vertebral and hip fractures are both seen in renal osteodystrophy and can be caused by abnormal bone quality (20). Bone quality is a recent term used to refer to the structural and material parameters that collectively enable bone to bear load and resist fracture or excessive deformation (21,22). The potential link between bone turnover and bone quality merits further study. Malluche et al. assessed bone quality in biopsies from dialysis patients with low and high turnover disease. Both types of turnover had impaired bone quality, although due to different mechanisms. This explains the observation that bone turnover has not consistently predicted fracture rates in the CKD population (23). Current imaging techniques and bone biomarkers are helpful in screening and longitudinally monitoring patients on dialysis. However, they still lack accuracy and specificity. Bone biopsy remains the gold standard for definitive diagnosis of the underlying type of renal osteodystrophy. KDIGO guidelines for performing bone biopsy in these patients are a reasonable attempt at maximizing the utility of this procedure in situations where definitive diagnosis is crucial as it may drastically alter the therapeutic plan. Short of these specific indications, it is needless to say that having accurate diagnosis with a bone biopsy on every dialysis patient is neither practical nor proven to alter long-term outcome. Further refinement and advent in various bone biomarkers and X-ray technology, may improve our diagnostic accuracy and minimize the need for a bone biopsy. On the other hand, if assessing bone fragility becomes an important aspect of the management of dialysis patients and using specific therapeutic tools to improve low bone turnover disease proves to be efficacious, then perhaps the indications for bone biopsy may in fact expand further. References 1. Moe S, Dr€ ueke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G: Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69(11):1945–1953, 2006 2. Hruska KA, Teitelbaum SL: Renal osteodystrophy. N Engl J Med 333:166–174, 1995 3. Monier-Faugere MC, Malluche HH: Trends in renal osteodystrophy: a survey from 1983 to 1995 in a total of 2248 patients. Nephrol Dial Transplant 11:111–120, 1996 4. Wang M, Hercz G, Sherrard DJ, Maloney NA, Segre GV, Pei Y: Relationship between intact 1–84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 26:836–844, 1995 5. Freemont T, Malluche HH: Utilization of bone histomorphometry in renal osteodystrophy: demonstration of a new approach using data from a prospective study of lanthanum carbonate. Clin Nephrol 63:138–145, 2005 6. Lehmann G, Ott U, Kaemmerer D, Schuetze J, Wolf G: Bone histomorphometry and biochemical markers of bone turnover in patients with chronic kidney disease stages 3–5. Clin Nephrol 70:296–305, 2008 7. Pereira RC, Juppner H, Azucena-Serrano CE, Yadin O, Salusky IB, Wesseling-Perry K: Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone 45:1161–1168, 2009 8. Sabbagh Y, Graciolli FG, O’Brien S, Tang W, dos Reis LM, Ryan S, Phillips L, Boulanger J, Song W, Bracken C, Liu S, Ledbetter S,
CALCIUM-BASED PHOSPHATE BINDERS
9.
10.
11.
12.
13.
14.
15.
Dechow P, Canziani ME, Carvalho AB, Jorgetti V, Moyses RM, Schiavi SC: Repression of osteocyte Wnt/beta-catenin signaling is an early event in the progression of renal osteodystrophy. J Bone Miner Res 27:1757–1772, 2012 Christov M, Pereira R, Wesseling-Perry K: Bone biopsy in renal osteodystrophy: continued insights into a complex disease. Curr Opin Nephrol Hypertens 22(2):210–215, 2013 Herberth J, Monier-Faugere MC, Mawad HW, Branscum AJ, Hwerberth Z, Wang G, Cantor T, Malluche HH: The five most commonly used intact parathyroid hormone assays are useful for screening but not for diagnosing bone turnover abnormalities in CKD-5 patients. Clin Nephrol 73(1):5–14, 2009 KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 76: S1–S130, 2009 Morrone LF, Russo D, Di Iorio B: Diagnostic workup for disorders of bone and mineral metabolism in patients with chronic kidney disease in the era of KDIGO guidelines. Int J Nephrol 2011:1–6, 2011 Adragao T, Herberth J, Monier-Faugere MC, Branscum AJ, Ferreira A, Frazao JM, Malluche HH: Femoral bone mineral density reflects histologically determined cortical bone volume in hemodialysis patients. Osteoporos Int 4:619–625, 2009 London G, Coyne D, Hruska K, Malluche HH, Martin KJ: The new kidney disease: improving global outcomes (KDIGO) guidelines-expert clinical focus on bone and vascular calcification. Clin Nephrol 74 (6):423–432, 2010 Erratum in: Clin Nephrol 80 (1): 80, 2013 Malluche HH, Mawad HW, Monier-Faugere MC: Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone
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biopsies in black and white patients. J Bone Miner Res 26:1368–1376, 2011 Bordier P, Rasmussen H, Marie P, Miravet L, Gueris J, Ryckwaert A: Vitamin D metabolites and bone mineralization in man. J Clin Endocrinol Metab 46:284–294, 1978 Malluche HH, Goldstein DA, Massry SG: Effect of 6 months therapy with 1,25 (OH)2D3 on bone disease of dialysis patients. Contrib Nephrol 18:98–104, 1980 Wesseling-Perry K, Pereira RC, Sahney S, Gales B, Wang HJ, Elashoff R, Juppner H, Salusky IB: Calcitriol and doxercalciferol are equivalent in controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism. Kidney Int 79:112–119, 2011 Trueba D, Sawaya BP, Mawad H, Malluche HH: Bone Biopsy: indications, Techniques, and Complications. Semin Dial 16(4):341–345, 2003 Danese MD, Kim J, Doan QV, Dylan M, Griffiths R, Chertow GM: PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis. Am J Kidney Dis 47(1):149–156, 2006 Burr DB: Bone quality: understanding what matters. J Musculoskelet Neuronal Interact 4:184–186, 2004 Felsenberg D, Boonen S: The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther 27:1–11, 2005 Malluche HH, Porter DS, Monier-Faugere MC, Mawad H, Pienkowski D: Differences in bone quality in low- and high-turnover renal osteodystrophy. J Am Soc Nephrol 23(3):525–532, 2012
Are Calcium-Based Phosphate Binders Ever Preferable in Dialysis Patients? Nishank Jain*† and Robert F. Reilly*† *Division of Nephrology, Department of Medicine, Veterans Affairs North Texas Health Care System, Dallas, Texas, and †Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
Several observational studies reported an association between hyperphosphatemia (serum phosphorus concentration >5.5 mg/dl) and adverse clinical outcomes including all-cause mortality, cardiovascular (CV) disease and vascular calcification (VC) in patients with end-stage renal disease (ESRD) (1). Given the limited ability of thrice-weekly hemodialysis (HD) to remove phosphorus (Pi), optimal control of serum Pi concentration in patients with ESRD can only be achieved by reducing gastrointestinal absorption. As aluminum-based binders fell out of favor, calcium-based binders became the drug of choice for Pi control in dialysis patients. Further advances in our understanding of potential adverse effects of excess calcium (Ca) load in ESRD patients along with the discovery of non-Ca-based Address correspondence to: Robert F. Reilly, MD, VA North Texas Health Care System, Nephrology Section, MC 111G1, 4500 South Lancaster Road, Dallas, TX 75216-7167, Tel.: (214) 857-1908, Fax: (214) 857-1514, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 269–272 DOI: 10.1111/sdi.12219 © 2014 Wiley Periodicals, Inc.
binders such as, sevelamer and lanthanum in late 1990s and early 2000s, lead to the question of whether calcium-based Pi binders should ever be preferred in patients with ESRD (2,3). We will address this issue by answering several questions. What Do We Know About Adverse Effects of Excess Calcium Load in Patients with ESRD? The higher risk of hip and vertebral fractures observed in patients with ESRD compared to age and gender-matched controls was thought to be secondary to negative calcium balance (4). It was postulated that Ca absorbed from calcium-based binders would offset negative Ca balance from the skeletal system. This theory draws further support from the recent decline in incidence of hip fractures in the ESRD population (4). However, other factors such as use of vitamin D analogues could also play a role. To examine whether there is net positive calcium flux into bone in patients with chronic kidney disease (CKD), a balance study was conducted in 8 CKD patients with estimated glomerular filtration rate (GFR)
El-Husseini and Sawaya
What is the Role of Bone Biopsy in the Management of Adult Dialysis Patients? Amr El-Husseini and Boutros Peter Sawaya Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky
Definitions and Classifications In 2005, Kidney Disease: Improving Global Outcomes (KDIGO) sponsored a conference entitled “Definition, Evaluation and Classification of Renal Osteodystrophy.” The results of this conference were published in 2006 (1). KDIGO introduced the term chronic kidney disease-mineral and bone disorder (CKD–MBD) and defined it as a “systemic disorder of mineral and bone metabolism due to CKD.” The traditional definition of renal osteodystrophy (ROD) did not accurately represent the diverse clinical spectrum of CKD–MBD. KDIGO guidelines recommended that the term “renal osteodystrophy” be restricted to describing the bone pathology associated with CKD that usually requires a bone biopsy for precise diagnosis. Based on studies that included histomorphometric analysis, an expanded classification system was developed at the consensus conference that took into account three distinctive parameters, the so-called TMV classification: turnover (T), measured by assessing bone-formation rate or activation frequency; mineralization (M), assessed by measuring unmineralized osteoid thickness and mineralization lag time; and bone volume (V). The TMV classification has expanded on the previously described histomorphometric abnormalities that included hyperparathyroid bone disease, adynamic bone disease, osteomalacia, and a mixture of an abnormal bone turnover and a defective mineralization (mixed uremic osteodystrophy) (2–6). Lack of Specificity in Bone Biomarkers and Other Noninvasive Tools Measurement of circulating parathyroid hormone (PTH) may not provide enough diagnostic information on the type of bone turnover, except perhaps
Address correspondence to: Peter Sawaya, MD, University of Kentucky, Division of Nephrology, Bone and Mineral Metabolism, 800 Rose St, MN 672, Lexington, KY 40536, Tel.: 859-323 2635, Fax: 859-257 3927, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 266–269 DOI: 10.1111/sdi.12236 © 2014 Wiley Periodicals, Inc.
for patients with extreme levels. It is beyond the scope of this brief communication to discuss in details the multiple reasons why there is a disconnection between PTH serum levels and bone turnover. But it is abundantly evident that bone turnover is affected by many other circulating as well as local factors (7,8). Furthermore, skeletal resistance to PTH and a remarkable variability in PTH assay hinder its prediction of the underlying bone turnover (9,10). Additionally, total alkaline phosphatase (ALP) and bone-specific ALP do not add much to the utility of PTH in predicting the underlying bone pathology (11). Other bone-derived turnover biomarkers are even less useful in dialysis patients since they tend to accumulate when renal function is decreased. In fact, KDIGO guidelines do not recommend the routine measurement of these biomarkers in CKD 3–5D (11). In contrast to the general population, the ability to predict fracture risk by measuring bone mineral density (BMD) in patients with CKD stages 3–5 is not yet confirmed (12). Moreover, BMD cannot distinguish between different types of renal osteodystrophy. Postmenopausal or age-related osteoporosis can be detected by BMD only at the earliest stages of CKD. In later stages and in the presence of CKD-MBD, the underlying decreased bone volume is better defined in the context of renal osteodystrophy and not osteoporosis (12). Femoral dual energy X-ray absorptiometry (DEXA) is a good noninvasive measure of cortical bone volume, but DEXA of the spine does not give reliable information on cancellous bone volume (13). Current evidence does not support a role for imaging in the diagnosis of renal bone disease in patients with CKD (14). Based on a systematic review of studies spanning over 20 years, abnormalities in bone mineralization are present in approximately 40% of adult patients on dialysis (11). In a more recent study, a mineralization defect was found in only 3% of 630 patients (15). The exact clinical implications of these abnormalities remain to be established. But older studies suggested potential association of mineralization defects with bone pain and fracture (16,17). It is interesting to observe that, at least in children, mineralization defects may persist despite suppression of secondary hyperparathyroidism with active vitamin D therapy (18).
267
BONE BIOPSY IN THE MANAGEMENT OF ADULT DIALYSIS PATIENTS
TABLE 1. Modified KDIGO proposed indications for bone biopsy in dialysis patients with rational and action plan Indication 1-Unexplained fractures and bone pain
Rational A-Identify precisely the degree of bone turnover
B-Assess bone volume
C-Assess for mineralization defects
D-Rule out micro-fractures E-Rule out aluminum deposition F-Diagnose unsuspected conditions: multiple myeloma, lymphoma, sarcoidosis, infection, etc. 2-Unexplained hypercalcemia
A- Possible HBT with moderate elevation of PTH B- Possible LBT with moderate elevation of PTH, with or without aluminum C- Diagnose unsuspected conditions (see 1F)
Action plan 1a-If high bone turnover (HBT), suppress PTH medically or surgically as deemed necessary. 1b-If low bone turnover (LBT), avoid active vitamin D therapy and calcium-containing phosphate binders, attempt aggressive control of serum phosphorus, consider lower calcium bath, encourage judicious weight-bearing exercises as tolerated and, when pertinent, be persistent in counseling for smoking cessation. 1c-If bone volume is very low with evidence of excessive resorption out of proportion to the degree of hyperparathyroid bone disease, then a search for potential causes (i.,e., underlying malignancy) is warranted and the use of anti-resorptive therapy that is appropriate for dialysis patient may be deemed necessary. 1d-If osteomalacia is present, a thorough search for possible causes is indicated (i.e., vitamin D deficiency, aluminum or fluorides accumulation, chronic hypophosphatemia, etc.) Treatment of underlying cause, including vitamin D therapy as appropriate. 1e-Treatment of the underlying cause (see 1a-1d &1f) 1f-Identify the source and institute chelation therapy 1g-Treatment of the underlying pathology
See 1a and 1c See 1b and 1f See 1c and 1g
3- Unexplained and persistent hypophosphatemia
A- Assess for mineralization defects
See 1d
4- Unexplained and persistent hyperphosphatemiaa (i.e., without evidence of noncompliance or severe hyperparathyroidism)
A- Possible HBT with moderate elevation of PTH. B- Possible LBT with moderate elevation of PTH
See 1a
5- Patients with divergent PTH and ALP results
A- Elevated ALP out of proportion to PTH: rule out underlying severe HPT or osteomalacia B- Moderate elevation in PTH with low AP: rule out LBT
See 1b See 1a, 1d and 1f
See 1b
6- Suspicion for osteomalacia
A- Presence of risk factors, symptoms, or elevated ALP
See 1d
7- Suspicion for aluminum-associated bone disease
A- History of exposure to aluminum, bone pain, muscle weakness, erythropoietinresistant microcytic anemia, hypercalcemia, neurological symptoms, elevated serum aluminum levels or positive deferoxamine test
See 1f
8- Prior to bisphosphonate therapy
A- Rule out LBT with absolute certainty as their use would be contraindicated.
See 1b
9- Prior to parathyroidectomya if the diagnosis is not clear or there is suspicion of underlying aluminum accumulation
A- Parathyroidectomy precipitously worsens aluminum bone disease.
See 1f
a
Not included in KDIGO guidelines.
268
El-Husseini and Sawaya
Limitations of Bone Biopsy in Clinical Practice While undoubtedly bone biopsy with histomorphometric analysis is the gold standard for defining bone abnormalities in dialysis patients, it is still a mere “snap shot” of a continuous and dynamic disease. Patients may go through phases with different abnormalities, or the initial changes may progress over time with various therapies and dialysis prescriptions. Repeated bone biopsies are certainly not practical or even acceptable as a valid “monitoring” tool. In addition, the technique of bone biopsy is not a required procedure for nephrologists to master nor it is in the curriculum of an interventional nephrology program. Finally, the number of centers with capability of performing comprehensive histomorphometric analysis on decalcified bone is limited. However, perhaps of all organ tissue subjected to analysis, bone is the most readily preserved and transported (19). Practical Indications for Bone Biopsy in Adult Dialysis Patients Bone biopsy is a minimally invasive procedure, but it is usually limited to certain settings where precise diagnosis may dictate a specific therapy or action plan (19). These indications are observed in relatively few patients and typically reflect extreme changes in bone pathology, as it is unrealistic to routinely collect bone biopsies from patients with CKD-MBD. In 2003 (and in this journal), we discussed potential indications for bone biopsy in end-stage renal disease patients (19). Very similar indications were put forth by the KDIGO guidelines in 2006 and updated in 2009 (1,11). The premise of the bone biopsy is that it is the most accurate tool for the diagnosis of renal osteodystrophy providing definitive TMV classification (11). While one cannot be dogmatic about these indications, they do provide a practical framework for clinicians to apply during their assessment of dialysis patients. KDIGO guidelines suggest that it is reasonable to perform a bone biopsy in the following various settings including, but not limited to: unexplained fractures, persistent bone pain, unexplained hypercalcemia, unexplained hypophosphatemia, possible aluminum toxicity, and prior to therapy with bisphosphonates in patients with CKD–MBD. These recommendations were not graded (11). In Table 1, we list modified KDIGO indications for bone biopsy and expand on the pathophysiologic rational behind performing the biopsy and how the results may direct further specific therapy or action plan. Future Directions and Conclusion In the future, bone biopsy may further assist in the management of dialysis patients by assessing
bone fragility. Vertebral and hip fractures are both seen in renal osteodystrophy and can be caused by abnormal bone quality (20). Bone quality is a recent term used to refer to the structural and material parameters that collectively enable bone to bear load and resist fracture or excessive deformation (21,22). The potential link between bone turnover and bone quality merits further study. Malluche et al. assessed bone quality in biopsies from dialysis patients with low and high turnover disease. Both types of turnover had impaired bone quality, although due to different mechanisms. This explains the observation that bone turnover has not consistently predicted fracture rates in the CKD population (23). Current imaging techniques and bone biomarkers are helpful in screening and longitudinally monitoring patients on dialysis. However, they still lack accuracy and specificity. Bone biopsy remains the gold standard for definitive diagnosis of the underlying type of renal osteodystrophy. KDIGO guidelines for performing bone biopsy in these patients are a reasonable attempt at maximizing the utility of this procedure in situations where definitive diagnosis is crucial as it may drastically alter the therapeutic plan. Short of these specific indications, it is needless to say that having accurate diagnosis with a bone biopsy on every dialysis patient is neither practical nor proven to alter long-term outcome. Further refinement and advent in various bone biomarkers and X-ray technology, may improve our diagnostic accuracy and minimize the need for a bone biopsy. On the other hand, if assessing bone fragility becomes an important aspect of the management of dialysis patients and using specific therapeutic tools to improve low bone turnover disease proves to be efficacious, then perhaps the indications for bone biopsy may in fact expand further. References 1. Moe S, Dr€ ueke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G: Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69(11):1945–1953, 2006 2. Hruska KA, Teitelbaum SL: Renal osteodystrophy. N Engl J Med 333:166–174, 1995 3. Monier-Faugere MC, Malluche HH: Trends in renal osteodystrophy: a survey from 1983 to 1995 in a total of 2248 patients. Nephrol Dial Transplant 11:111–120, 1996 4. Wang M, Hercz G, Sherrard DJ, Maloney NA, Segre GV, Pei Y: Relationship between intact 1–84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 26:836–844, 1995 5. Freemont T, Malluche HH: Utilization of bone histomorphometry in renal osteodystrophy: demonstration of a new approach using data from a prospective study of lanthanum carbonate. Clin Nephrol 63:138–145, 2005 6. Lehmann G, Ott U, Kaemmerer D, Schuetze J, Wolf G: Bone histomorphometry and biochemical markers of bone turnover in patients with chronic kidney disease stages 3–5. Clin Nephrol 70:296–305, 2008 7. Pereira RC, Juppner H, Azucena-Serrano CE, Yadin O, Salusky IB, Wesseling-Perry K: Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone 45:1161–1168, 2009 8. Sabbagh Y, Graciolli FG, O’Brien S, Tang W, dos Reis LM, Ryan S, Phillips L, Boulanger J, Song W, Bracken C, Liu S, Ledbetter S,
CALCIUM-BASED PHOSPHATE BINDERS
9.
10.
11.
12.
13.
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Are Calcium-Based Phosphate Binders Ever Preferable in Dialysis Patients? Nishank Jain*† and Robert F. Reilly*† *Division of Nephrology, Department of Medicine, Veterans Affairs North Texas Health Care System, Dallas, Texas, and †Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
Several observational studies reported an association between hyperphosphatemia (serum phosphorus concentration >5.5 mg/dl) and adverse clinical outcomes including all-cause mortality, cardiovascular (CV) disease and vascular calcification (VC) in patients with end-stage renal disease (ESRD) (1). Given the limited ability of thrice-weekly hemodialysis (HD) to remove phosphorus (Pi), optimal control of serum Pi concentration in patients with ESRD can only be achieved by reducing gastrointestinal absorption. As aluminum-based binders fell out of favor, calcium-based binders became the drug of choice for Pi control in dialysis patients. Further advances in our understanding of potential adverse effects of excess calcium (Ca) load in ESRD patients along with the discovery of non-Ca-based Address correspondence to: Robert F. Reilly, MD, VA North Texas Health Care System, Nephrology Section, MC 111G1, 4500 South Lancaster Road, Dallas, TX 75216-7167, Tel.: (214) 857-1908, Fax: (214) 857-1514, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 269–272 DOI: 10.1111/sdi.12219 © 2014 Wiley Periodicals, Inc.
binders such as, sevelamer and lanthanum in late 1990s and early 2000s, lead to the question of whether calcium-based Pi binders should ever be preferred in patients with ESRD (2,3). We will address this issue by answering several questions. What Do We Know About Adverse Effects of Excess Calcium Load in Patients with ESRD? The higher risk of hip and vertebral fractures observed in patients with ESRD compared to age and gender-matched controls was thought to be secondary to negative calcium balance (4). It was postulated that Ca absorbed from calcium-based binders would offset negative Ca balance from the skeletal system. This theory draws further support from the recent decline in incidence of hip fractures in the ESRD population (4). However, other factors such as use of vitamin D analogues could also play a role. To examine whether there is net positive calcium flux into bone in patients with chronic kidney disease (CKD), a balance study was conducted in 8 CKD patients with estimated glomerular filtration rate (GFR)
