Synonyms and keywords:Chronic kidney disease- mineral bone disorder
Overview
Renal osteodystrophy (ROD) is within the broad spectrum of Chronic Kidney Disease (CKD)- Mineral Bone Disease (MBD). The disease occurs as a natural complication of the CKD and is characterized by abnormal levels and metabolism of calcium (Ca), phosphorus (Ph), parathyroid Hormone (PTH), and vitamin D, as well as calcification of soft tissues and bone turn over and mineralization abnormalities. Secondary hyperparathyroidism and 1,25-dihydroxycholecalciferol (vitamin D3) deficiency play a major role in ROD. Any factor leading to CKD is potentially a risk factor for ROD. Hypocalcemia, hyperphosphatemia, vitamin D deficiency, parathyroid glandhyperplasia and acidosis are the other contributors of ROD. Aluminum related ROD is mostly seen in patients who undergo dialysis. ROD is an important cause of morbidity, decreased quality of life, and extravascular calcifications that have been associated with increased cardiovascular mortality. Primary investigation of ROD includes measurement of blood levels of parathyroid hormone (PTH), calcium, phosphorus, alkaline phosphatase and bicarbonate. Imaging studies should focus on finding calcification in soft tissues. A bone biopsy is indicated if the results of biochemical markers are not consistent or when there is unexplained bone pain, or in case of presence of unexplained bone fractures. However, bone biopsies are infrequently used in clinical practice due to invasiveness and low cost-effectiveness. Common complications of ROD include bone fractures and vascular calcifications leading to atherosclerosis, coronary artery calcification, hypertension, left ventricular hypertrophy, and congestive heart failure (CHD). Extra-skeletal calcification can also affect the heart valves and the cardiac conduction system. Calcification of skin arterioles may lead to a condition of ischemia and necrosis of the skin known as calciphylaxis. Patients with renal osteodystrophy usually present with bone pain, arthralgia, chest pain, dyspnea, and palpitation. Physical examination of patients with renal osteodystrophy may include bone deformity, bone fracture, hypertension, ongestive heart failure, heart murmur, increased pulse pressure (due to aortic calcification) and skin ischemia and necrosis. In laboratory findings, serum calcium levels are typically low. Serum phosphorous is elevated depending on the stage of chronic kidney disease, dietary phosphorous, and use of phosphate binders. Alkaline phosphatase levels (total or bone-specific) are elevated and show increased osteoblastic activity. High levels of alkaline phosphatase are seen in severe osteitis fibrosa. Elecrocardiographic findings in patients with renal osteodystrophy include heart block and non-ST-elevation myocardial infarction. Radiographic findings are less sensitive for diagnosis compared to parathyroid hormone levels. Imaging is usually performed for patients with unexplained bone pain or fractures. Radiographic findings of osteitis fibrosa cystica include subperiosteal resorption. Resorptive loss of bone may be seen at the terminal phalanges, distal ends of the clavicles, and in the skull. Radiographs will show soft tissue calcification that involves the vasculature. Phosphate binders and supplemental calcium are mainly used for prevention and treatment of renal osteodystrophy. The major objective in the prevention and management of renal osteodystrophy is either prevention of hyperparathyroidism or its treatment if present.
Historical Perspective
Renal osteodystrophy was first defined by Kidney Disease: Improving Global Outcomes (KDIGO) in 2006.
In CKD, serum Ca levels decrease and serum Ph levels increase. Initially in the course of renal disease, compensatory mechanisms try to increase serum Ca and decrease serum Ph. These mechanisms include increased levels of fibroblast growth factor 23 (FGF23) which in turn increases urinary Ph excretion. On the other hand, increased PTH levels further increase urinary excretion of Ph. However, as the renal disease becomes chronic, these compensatory mechanisms do not respond any more and the characteristic features of ROD become evident [5]. Once an abnormality in serum levels of these minerals is established (decreased Ca and increased Ph), PTH levels increase and change bone metabolism via alterations in osteoblast and osteoclast activity. Early in CKD, due to increased FGF23, 1,25 (OH) vitamin D decreases which further leads to hyperparathyroidism (HPTH). However, some contributors to CKD-MBD alter before PTH levels are increased, an example of these contributors are sclerostin and FGF23 which are increased even before HPTH. HPTH can also insert its effects via the reduction of β-catenin which inhibits maturation of osteoblasts.
PTH receptors are found on preosteoblasts, osteoblasts and osteocytes and increases their proliferation. (Osteoclasts do not have PTH receptors and are activated by preosteoblasts and osteoblasts.)
Increased levels of PTH lead to increased bone resorption by osteoclasts [6] and osteitis fibrosa.
As a result, HPTH leads to high-turnover bone disease.
Many factors can contribute to low levels of PTH, such as increased dietary intake of Ca and Vit D, using Ph binders containing Ca dialysate. Low levels of PTH lead to low-turnover bone disease, also known as adynamic bone disease. Low PTH levels lead to excess circulating Ca (since Ca is not deposited in the bone). This excess Ca may lead to calcification of soft tissues.
Aluminum-based chelation of Ph during dialysis was among the common factors contributing to osteomalacia. However since replacement of aluminum with other chelators this factor is less prominent. [4][7][2]
CKD leads to uremia and hyperphosphatemia which change the pluripotent smooth muscle cells to osteoblasts. This coupled with increased Ca levels leads to calcification of soft tissues [8].
Overall, following factors contribute to vascular calcification [5]:
Hypocalcemia and hyperphosphatemia
Hyperparathyroidemia
Matrix degradation and alteration of matrix proteins
Apoptosis of smooth muscle cells
Systemic inflammation
Factors in the pathogenesis of hyperparathyroidism in chronic renal disease
The prevalence of renal osteodystrophy in developing countries is 24.4% to 63%.
Aluminum, increased strontium levels and high levels of iron in the blood play a major role in the development of renal osteodystrophy in patients who undergo dialysis in developing countries.
Extraskeletal manifestations of CKD-MBD (calcification of soft tissues) is observed in 1000 per 100,000 of CKD patients on dialysis.
Risk Factors
Any factor leading to CKD, indirectly leads to renal osteodystrophy. These factors include:
Microscopic pathology of bone marrow biopsy in a patient with chronic kidney disease. Increased areas of bone absorption are seen due to increased osteoclastic activity. Courtesy of image from https://www.flickr.c[10]om/photos/bc_the_path/537039421/in/photolist-Pst7n.A definitive tool for diagnosis of renal osteodystrophy is bone biopsy according to KIDGO 2017 guidelines.[3]
However, bone biopsies are infrequently performed because it is an invasive and expensive procedure.
Bone biopsy results can be summerized in following pathologic categories.[1]
Measurement of bone turnover on a bone biopsy is determined by labeling the bone with tetracycline. The procedure is done at two separate times approximately 2 weeks apart. The distance between the two areas of tetracycline deposition is measured and can be used to calculate bone growth.
Intermediate PTH levels between 100 and 450 pg/mL. Intermediate values may be associated with normal or increased bone turnover or even reduced turnover.[3]
↑Moe, S.; Drüeke, T.; Cunningham, J.; Goodman, W.; Martin, K.; Olgaard, K.; Ott, S.; Sprague, S.; Lameire, N.; Eknoyan, G. (2006). "Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)". Kidney International. 69 (11): 1945–1953. doi:10.1038/sj.ki.5000414. ISSN0085-2538.
↑Jorge B, Cannata-Andνa, Minerva Rodrνguez-Garcνa; et al. (2006). "ascular calcifications: Pathogenesis, management and impact on clinical outcomes". J Am Soc Nephrol. 17: 267–73.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
↑Nissenson, Allen (2009). Current diagnosis & treatment. New York: McGraw-Hill Medical. ISBN978-0-07-144787-4.
↑Abdullah M.W. El-Kishawi*, A.M. El-Nahas (2006). "Renal Osteodystrophy: Review of the Disease and its Treatment". Saudi J Kidney Dis Transplant. 17 (3): 373–382.