| Abstract|| |
Renal osteodystrophy (ROD) is not a uniform bone disease; it is a heterogeneous group of metabolic bone diseases due to chronic kidney disease (CKD). The traditional term of ROD does not accurately include the wide spectrum of “CKD–mineral and bone disorder” (CKD–MBD) and has been restricted to define the several specific histologic disturbances of bone disease associated with CKD. Circulating parathyroid hormone (PTH) and total alkaline phosphatase levels do not always reflect bone turnover in CKD–MBD, whereas bone biopsy provides precise information regarding bone pathology. Given the lack of specificity of several biomarkers and noninvasive tools regarding ROD, bone biopsy is required for precise diagnosis and for the determination of therapeutic strategies. In clinical practice, bone biopsy is not performed due to lack of enthusiasm among nephrologists for several reasons including the invasiveness of the procedure, the potential pain, and lack of technical training. Since the application of bone biopsy in clinical practice is unrealistic, several biomarkers with specificity for bone disease should be studied.
|How to cite this article:|
Dousdampanis P, Trigka K. The importance of bone biopsy in chronic kidney disease–Mineral bone disorders. Saudi J Kidney Dis Transpl 2017;28:992-6
|How to cite this URL:|
Dousdampanis P, Trigka K. The importance of bone biopsy in chronic kidney disease–Mineral bone disorders. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2018 Aug 15];28:992-6. Available from: http://www.sjkdt.org/text.asp?2017/28/5/992/215150
| Introduction|| |
Bones are not static, are inert structures, and are dynamic undergoing adaptation to achieve and maintain the skeletal size, quality, and strength. Besides the role of bones in locomotion, they participate in mineral metabolism, acid-base equilibrium, and are essential for the hematopoietic system. Recently, more attention has been given to the interaction of bones with the cardiovascular system in respect to survival of patients with chronic kidney disease (CKD). CKD at advanced stages is characterized by progressive alterations in mineral metabolism and bone remodeling. In addition, cardiovascular calcifications due to bone disorders contribute to increased mortality in CKD patients.
In 1973, Ritz et al introduced the term “mixed uremic osteodystrophy,” after 33 years the Kidney Disease: Improving Global Outcomes (KDIGO) has introduced the term “CKD–mineral and bone disorder (CKD– MBD).” According to the KDIGO, the CKD–MBD describes a clinical syndrome encompassing mineral, bone, and calcific cardiovascular abnormalities.
The old term “renal osteodystrophy (ROD)” did not represent the wide spectrum of CKD–MBD and hence, ROD is restricted to define the several histologic forms of bone pathology associated with CKD.
Based on the histomorphometric analysis of bone biopsy, an expanded classification system was introduced to describe bone pathology, the so-called TMV classification named by the first letters of turnover (T), mineralization (M), and volume (V). According to the TMV classification, ROD includes hyperpara-thyroid bone disease, adynamic bone disease, osteomalacia, and mixed uremic osteodystrophy (mixture of both defective turnover and mineralization). Due to the lack of specificity and sensitivity of several biomarkers for bone pathology and noninvasive tools for CKD–MBD, the KDIGO recommends bone biopsy and histologic evaluation of histomorpho-metric analyses including static and dynamic parameters as the gold standard diagnostic test for ROD.
| Decreased Specificity of Bone Biomarkers and Imaging Tools|| |
In clinical practice, measurements of circulating parathyroid hormone (PTH) are not always diagnostic of ROD. In addition, PTH levels cannot replace bone histology for the diagnosis of ROD; PTH values do not provide any information regarding bone volume and mineralization status. Both skeletal resistance to PTH and variability in PTH assay hinder the predictive value of PTH for bone turnover.
In addition, total alkaline phosphatase (ALP) and bone-specific ALP do not confer more information regarding bone turnover. Interestingly, several suggested biomarkers of bone turnover are even less useful in the diagnosis of CKD–MBD.
Bone mineral density (BMD) is seen in all types of ROD and it cannot be used as a diagnostic tool to distinguish between the several types of ROD. BMD can detect post-menopausal osteoporosis at the earliest stages of CKD, but its ability to predict fracture risk at advanced CKD stages is not yet confirmed. Femoral dual-energy X-ray absorptiometry (DEXA) is a useful noninvasive measure only of cortical bone volume and does not measure cancellous bone volume. DEXA and highresolution peripheral quantitative computed tomography give information regarding the mass and quality of bone, but they do not measure turnover or mineralization and hence, they cannot be used to determine ROD. Thus, current evidence does not support any role for imaging tools in the diagnosis of CKD–MBD.,,
| Indications, Contraindications, and Complications of Bone Biopsy|| |
Nephrologists should not hesitate to proceed to bone biopsy because it is a minimally invasive procedure. Lack of technical training and specialized centers that interpret bone sample, in combination with the potential pain to the patient and the increased cost, prevents carrying out bone biopsy in routine clinical practice. The anterior iliac crest is the most common site used for bone biopsy because it is easily accessible and the rate of complications is lower.
According to a European Survey, the total number of bone biopsies performed in the past five years has been very low (being <10). In most European nephrology centers, bone biopsies were performed for research purpose in 27.2% of the cases. Interestingly, only 58.9% of bone biopsies were performed by nephrologists.
Patients with CKD have an increased risk of fractures. In addition, bone fractures increase both mortality and health costs in CKD patients., Low impact fracture, unexplained bone pain or unexplained hypercalcemia, and initiation of antiresorptive drugs for osteoporosis (bisphosphonates should not be prescribed in the presence of low bone turnover), before parathyroidectomy to confirm high bone turnover and radiologic abnormalities, are some common indications for performing bone biopsy in CKD patients.,
In the past, bone biopsy was performed in cases of suspected overload or toxicity of aluminum, but the use of aluminum-free hemodialysis water and nonaluminum-containing phosphate binders has dramatically reduced aluminum toxicity.
Bone biopsy is indicated in dialysis patients with progressively rapid and unexplained calcifications, as well as in dialysis patients with suspected calciphylaxis.
Interestingly, 70%–90% of patients with CKD stages 3–4 also present changes in bone and mineral metabolism. In addition, some of them may have underlying bone disease before the development of CKD due to the use of corticosteroids as in cases of glomerulonephritis, osteoporosis, or Vitamin D deficiency. Thus, there is a need to better define the bone abnormalities in patients with CKD stages 3–4 to facilitate appropriate treatment decisions.
In this respect, the risk of bone fractures is increased after transplantation due to preexisting ROD and/or decreased BMD and osteoporosis because of the use of calcineurin inhibitors and corticosteroids.
The indications for bone biopsy are based on clinical, biochemical, and radiologic abnormalities.,, In addition, bone biopsy is performed for research purposes. [Table 1] summarizes the principal indications for bone biopsy as recommended by the KDIGO.
|Table 1: Indications for bone biopsy in patients with chronic kidney disease.|
Click here to view
Usually, bone biopsy in CKD is not contra-indicated except in cases of coagulation disorders, soft tissue and/or skin inflammation, and the presence of local infection (over the iliac area). The percentage of complications following bone biopsy is very low. Intolerance, allergic reaction, and gastrointestinal disorders have been reported after intake of antibiotics for bone labeling. Bleeding, local bruising, pain, neuropathy, infection, fracture, and osteomyelitis have also been reported.,
| Bone Histomorphometric Parameters in Renal Osteodystrophy|| |
Several bone histomorphometric parameters are obtained using commercialized computerized image analysis systems. Parameters of bone mass, static parameters of bone formation and resorption, and dynamic parameters of both bone formation and mineralization are included in the analysis of cancellous bone.
The first bone histomorphometric analysis of bone biopsy in CKD patients was based on turnover, the percentage of osteoid, and the presence (or not) of fibrosis.
According to histomorphometric analysis, three types of ROD have been recognized: (a) high turnover bone disease including hyperparathyroidism or osteitis fibrosa cystica, (b) low turnover bone disease including adynamic bone disease or osteomalacia, and (c) mixed uremic osteodystrophy characterized as high turnover bone disease in association with mineralization defect.
Histomorphometric parameters are obtained numerically using several computerized image analysis systems such as Bioquant Osteo 2011, OsteoMeasure, and Semiautomatic Image Analysis.
The most commonly used histomorphometric parameters are subdivided into: (a) structural parameters, indicating the overall size of the biopsy specimen, the distance between periosteal and endocortical surfaces, core and cortical width, and the unmineralized bone, (b) static formation parameters, indicating the percentage of the bone surface covered by osteoid, the percentage of bone volume, and the percentage of bone surface covered by osteoblasts, (c) dynamic formation parameters, indicating percentage of bone surface with mineralizing activity and amount of bone formed per year, and (d) static resorption parameters, indicating the percentage of bone surface covered by osteoclasts. [Table 2] summarizes the principal abnormalities of the histo-morphometric parameters observed in ROD.
|Table 2: Principal histomorphometric parameters of bone biopsy in chronic kidney disease patients.|
Click here to view
| Conclusions and Perspectives|| |
The diagnosis of ROD cannot be obtained correctly by the use of current biochemical and imaging tools. Bone biopsy still remains the gold standard for the precise diagnosis of ROD. However, nephrologists should be trained to perform bone biopsy and they should not hesitate to proceed with it when necessary.
However, since performing bone biopsy is unrealistic in routine clinical practice, new bone turnover biomarkers with high specificity and sensitivity should be studied to diagnose ROD in CKD patients.
Conflict of interest: None declared.
| References|| |
Torres PU, Bover J, Mazzaferro S, de Vernejoul MC, Cohen-Solal M. When, how, and why a bone biopsy should be performed in patients with chronic kidney disease. Semin Nephrol 2014;34:612-25.
Smith ER. Vascular calcification in uremia: New-age concepts about an old-age problem. Methods Mol Biol 2016;1397:175-208.
London GM, Marchais SJ, Guérin AP, Métivier F. Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia. Curr Opin Nephrol Hypertens 2005;14:525-31.
Ritz E, Krempien B, Mehls O, Malluche H. Skeletal abnormalities in chronic renal insufficiency before and during maintenance hemodialysis. Kidney Int 1973;4:116-27.
Moe S, Drüeke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: A position statement from kidney disease: Improving global outcomes (KDIGO). Kidney Int 2006;69:1945-53.
Herberth J, Monier-Faugere MC, Mawad HW, et al. 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 2009;72:5-14.
El-Husseini A, Sawaya BP. What is the role of bone biopsy in the management of adult dialysis patients? Semin Dial 2014;27:266-9.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009;113:S1-130.
Babayev R, Nickolas TL. Can one evaluate bone disease in chronic kidney disease without a biopsy? Curr Opin Nephrol Hypertens 2014;23:431-7.
Trueba D, Sawaya BP, Mawad H, Malluche HH. Bone biopsy: Indications, techniques, and complications. Semin Dial 2003;16:341-5.
Evenepoel P, D’Haese P, Bacchetta J, et al. Bone biopsy practice patterns across Europe: The European renal osteodystrophy initiative-a position paper. Nephrol Dial Transplant 2017;doi:10.1093.
Mittalhenkle A, Gillen DL, Stehman-Breen CO. Increased risk of mortality associated with hip fracture in the dialysis population. Am J Kidney Dis 2004;44:672-9.
Tentori F, McCullough K, Kilpatrick RD, et al. High rates of death and hospitalization follow bone fracture among hemodialysis patients. Kidney Int 2014;85:166-73.
Gal-Moscovici A, Sprague SM. Role of bone biopsy in stages 3 to 4 chronic kidney disease. Clin J Am Soc Nephrol 2008;3 Suppl 3:S170-4.
Nikkel LE, Hollenbeak CS, Fox EJ, Uemura T, Ghahramani N. Risk of fractures after renal transplantation in the United States. Transplantation 2009;87:1846-51.
Sherrard DJ, Baylink DJ, Wergedal JE, Maloney NA. Quantitative histological studies on the pathogenesis of uremic bone disease. J Clin Endocrinol Metab 1974;39:119-35.
Rauch F. Bone biopsy: Indications and methods. Endocr Dev 2009;16:49-57.
Hemodialysis Unit Kyanos Stavros, Germanou 115, Patras, 26224
[Table 1], [Table 2]