 |
|||||||||
|
|||||||||
| CECIL |
| TEXT BOOK of MEDICINE |
Section XI Renal and Genitourinary Diseases
| 132 RENAL OSTEODYSTROPHY Keith A. Hruska • |
|
|
Definition
Renal osteodystrophy (ROD) is a disorder of skeletal remodeling resulting from injury to the kidney, especially as seen in chronic kidney disease (CKD) (Chapter 131). The manifestations of ROD are proportional to the severity of renal injury. In end-stage kidney disease (ESKD) (Chapter 133), stage 5 in the Kidney Disease Outcomes Quality Initiative (K/DOQI) classification, some manifestation of the disorder is expressed in the great majority of patients. ROD encompasses a wide variety of derangements in mineral and bone metabolism, and it directly contributes to the excess cardiovascular mortality associated with CKD.
The earliest histologic abnormalities of bone in ROD are seen after a relatively mild reduction in the glomerular filtration rate (creatinine clearance between 40 and 70 mL/min, stage 2 CKD). By the time that ESKD develops, skeletal histologic pathology is found in virtually all patients. The increasing incidence of CKD and ESKD in the United States and the role of ROD in their high mortality make ROD a major health issue for Americans and all developed societies.
Pathobiology
Pathogenesis
Renal injuries produce a loss of skeletal anabolism manifested as a decrease in bone formation derived from osteoblast activity. The loss of anabolism may represent decreased influence of a hormonal factor or increased activity of an inhibitory principle. The effect is loss of influence of either bone morphogenetic proteins (BMPs) or wingless/ints proteins (Wnts) on osteoblast activity after renal injury. Because osteoblasts are the hematopoietic stem cell niche, an adaptation to the loss of anabolism is required to preserve hematopoiesis. This adaptation is secondary hyperparathyroidism. Three principles—BMPs, Wnts, and parathyroid hormone (PTH)—regulate the hematopoietic stem cell niche. Loss of osteoblastic bone formation secondary to renal injury shrinks the size of the rapidly exchangeable phosphate and calcium pools and causes early secondary hyperparathyroidism as a result of adapting to maintain the niche size; such adaptation is achieved at the expense of high PTH levels and the influence of secondary hyperparathyroidism on skeletal remodeling.
As kidney failure advances, a variety of factors directly stimulate PTH secretion, including hypocalcemia, low levels of circulating calcitriol (the hormonal vitamin D metabolite), hyperphosphatemia, and others. These factors are additive to the initial stimulus produced by renal injury. The initial stimulus to hyperparathyroidism by renal injury is demonstrated in some patients with mild chronic kidney failure who exhibit increased serum PTH levels without alterations in fasting serum levels of calcium, phosphorus, or calcitriol.
Early Kidney Failure
The early sequence of events in ROD remains to be fully defined. However, early stages of kidney failure can be shown to decrease bone formation rates and osteoblast surfaces when normal Ca, Pi, PTH, and vitamin D levels are maintained. This loss of anabolism causes an adaptive hyperparathyroidism in an attempt to maintain normal osteoblastic function. However, higher than normal PTH levels are required in the new abnormal skeletal environment because of loss of osteoblastic anabolism from the BMPs or Wnts. The function of PTH in this setting is to maintain homeostasis of hematopoiesis and the skeleton through regulation of the hematopoietic stem cell niche and skeletal remodeling. The hematopoietic stem cell is the target of another renal hormone, erythropoietin, produced by the kidney in response to its function as the body's oxygen sensor. Thus, it is not surprising that the kidney produces an osteoblast anabolic principle that has yet to be defined because it is necessary to maintain the niche of the erythropoietin target, the hematopoietic stem cell. Disturbances in stem cell function threaten the homeostasis of hematopoiesis and may contribute to the abnormalities in immunity that complicate CKD. The sustained increased PTH levels achieved through adaptation to CKD produce an unwanted disorder of skeletal remodeling, high-turnover ROD, also referred to as osteitis fibrosa.
Advanced Kidney Failure
As renal injuries advance and more significant reductions in the glomerular filtration rate result, classic changes in vitamin D metabolism and divalent ion homeostasis develop and are associated with the pathogenesis of secondary hyperparathyroidism in CKD. These changes are loss of capacity in calcitriol production, decreased calcium absorption leading to hypocalcemia, and a decrease in phosphate excretion leading to hyperphosphatemia.
Pathogenetic Factors in Secondary Hyperparathyroidism
CALCITRIOL DEFICIENCY. As CKD advances, the functioning nephron mass is decreased, which when combined with an increased phosphate load in the remaining nephrons and perhaps increased fibroblast growth factor-23 (FGF-23) levels, results in decreased production of calcitriol by proximal tubular 25-hydroxycholecalciferol 1a-hydroxylase. Calcitriol deficiency in turn decreases intestinal calcium absorption and leads to hypocalcemia. Calcitriol deficiency in cases of advanced kidney failure diminishes tissue levels of vitamin D receptors (VDRs), in particular, VDRs in the parathyroid glands. Because the chief cell VDR suppresses the expression of pre-pro-PTH messenger RNA (mRNA), lower circulating calcitriol levels together with a low number of VDRs in patients with ESKD result in stimulation of both synthesis and secretion of PTH.
HYPOCALCEMIA. As CKD progresses, hypocalcemia develops as a result of decreased intestinal Ca absorption. Low blood levels of ionized calcium stimulate PTH secretion, whereas high calcium concentrations suppress it. The action of calcium on parathyroid gland chief cells is mediated through a calcium sensor—a G protein–coupled plasma membrane receptor expressed in chief cells, in kidney tubular epithelia, and widely throughout the body at lower levels. The short-term stimulation of PTH secretion induced by low calcium is due to exocytosis of the PTH packaged in granules, and longer-term stimulation results from an increase in the number of cells that secrete PTH. More prolonged hypocalcemia induces changes in intracellular PTH degradation and mobilization of a secondary storage pool. Within days or weeks of the onset of hypocalcemia, pre-pro-PTH mRNA expression is stimulated. This effect is exerted through a negative calcium response element located in the upstream flanking region of the gene for PTH. Expression of the calcium receptor is suppressed by calcitriol deficiency and stimulated by calcitriol administration, thus suggesting an additional regulatory mechanism of the active vitamin D metabolite on PTH production. The decreased number of calcium-sensing receptors with low circulating calcitriol levels may, at least in part, explain the relative insensitivity of parathyroid gland cells to calcium in patients undergoing dialysis.
HYPERPHOSPHATEMIA. As renal injury decreases nephron numbers, the stimulus to hyperphosphatemia is reversed through PTH- and perhaps FGF-23–mediated reductions in tubular epithelial phosphate transport. The increase in phosphate excretion per remaining nephron restores phosphate homeostasis at the cost of higher PTH and FGF-23 levels. When renal injury is severe enough that the glomerular filtration rate is less than 30% of normal (stages 4 and 5 CKD), hyperphosphatemia becomes fixed because of insufficient renal excretion despite high PTH and FGF-23 levels. At this reduced renal function, the ability of the remaining nephrons to increase phosphate excretion above roughly 75% of the filtered load fails for unclear reasons. Recent studies have demonstrated that failure of phosphorus deposition in the skeleton or excess resorption of the skeleton also contributes to the hyperphosphatemia seen in patients with CKD and ESKD. Hyperphosphatemia decreases serum calcium through physicochemical binding and suppresses 1α-hydroxylase activity, which results in further lowering of circulating calcitriol levels. Moreover, a direct stimulatory effect of phosphorus on parathyroid gland cells, independent of calcium and calcitriol, produces increased secretion and nodular hyperplasia of parathyroid gland cells. Finally, hyperphosphatemia is a signaling mechanism for induction of heterotopic mineralization of the vasculature in CKD and ESKD.
HYPERPARATHYROIDISM. All of the mechanisms just discussed result in increased production of PTH and increased parathyroid gland mass. The size of the parathyroid glands progressively increases during CKD and in dialyzed patients in parallel with serum PTH levels. This increase in gland size is mainly due to diffuse cellular hyperplasia. Monoclonal chief cell growth also develops and results in the formation of nodules. Nodular hyperplastic glands have fewer VDRs and calcium-sensing receptors than diffusely hyperplastic glands do, thereby promoting parathyroid gland resistance to calcitriol and calcium. Sustained elevations in PTH levels, though adaptive to maintain osteoblast surfaces, produce an abnormal phenotype of osteoblast function with relatively less type 1 collagen and more RANKL ligand production than is the case with anabolic osteoblasts. This leads to high-turnover osteodystrophy, desensitization of PTH receptors, and excess bone resorption.
FIBROBLAST GROWTH FACTOR-23. FGF-23 is the original phosphatonin (phosphate excretion–regulating hormone) discovered in studies of inherited hypophosphatemia and oncogenic osteomalacia. FGF-23 levels progressively rise during the course of CKD, but the role of FGF-23 in regulating phosphate homeostasis in CKD and calcitriol synthesis has not been fully elucidated. Furthermore, FGF-23 is produced mainly by osteoblasts, and it is a mineralization inhibitor. It is unclear whether FGF-23 contributes to the mineralization defects in skeletal remodeling observed in CKD.
INFLAMMATORY MEDIATORS. CKD is well known as an inflammatory state with elevated levels of numerous inflammatory cytokines, chemokines, and their receptors. For instance, interleukin-8 (IL-8) levels are elevated and contribute to PTH secretion. A central inflammatory cytokine, IL-6, is a direct marker of inflammation in CKD and contributes to the pathogenesis of ROD, but the critical roles of inflammatory mediators in ROD remain to be defined.
ALUMINUM. Accumulation of aluminum (Al+3) in bone and other organs such as the parathyroid glands may occur in patients with moderate or severe renal disease or in those undergoing dialysis. Aluminum accumulation in the parathyroid glands results in decreased secretion of PTH and suppression of bone turnover. In addition, Al+3 inhibits renal and intestinal 25-hydroxycholecalciferol 1α-hydroxylase activity, and thus Al+3 may further contribute to reduced levels of calcitriol. Possible sources of aluminum include high concentrations in the water used for dialysis, prescription of aluminum-containing phosphate binders, and aluminum in drinking water, infant formula, and other liquids or solid food.
ACIDOSIS. As nephron mass declines in CKD, the ability to regenerate bicarbonate consumed in the buffering of metabolic acids is lost. As a result, metabolic acidosis is a uniform finding in stage 4 and 5 CKD. In this setting, bone becomes an important buffer of acid production in patients with ESKD. Metabolic acidosis stimulates bone resorption and suppresses bone formation, thereby resulting in negative bone balance and contributing significantly to the pathogenesis of ROD.
HYPOGONADISM. Patients with ESKD have various states of gonadal dysfunction. Estrogen and testosterone deficiency significantly contributes to the pathogenesis of ROD.
OTHER FACTORS. Some patients with CKD are treated with glucocorticoids, which have an impact on bone metabolism. Patients maintained on chronic dialysis have retention of β2-microglobulin, which causes a distinct arthropathy. Additionally, alterations in growth factors and other hormones involved in the regulation of bone remodeling may be disordered in CKD/ESRD, thus affecting bone remodeling and contributing to the development of ROD.
Pathology
ROD is not a uniform disease. Depending on the relative contribution of the different pathogenic factors discussed earlier, various pathologic patterns of bone remodeling are expressed in CKD and ESKD.
Predominant Hyperparathyroid Bone Disease, High-Turnover Renal Osteodystrophy, Osteitis Fibrosa
Sustained excess PTH results in increased bone turnover. Osteoclasts, osteoblasts, and osteocytes are found in abundance (Fig. 132-1). Disturbed osteoblastic activity results in a disorderly production of collagen, which leads to the formation of woven bone. Accumulation of fibroblastic osteoprogenitors not in the osteoblastic differentiation program results in collagen deposition (fibrosis) in the peritrabecular and marrow space. The nonmineralized component of bone, osteoid, is increased, and the normal three-dimensional architecture of osteoid is frequently lost. Osteoid seams no longer exhibit their usual birefringence under polarized light; instead, a disorderly arrangement of woven osteoid and woven bone with a typical crisscross pattern under polarized light is seen. The mineral apposition rate and the number of actively mineralizing sites are increased, as documented under fluorescent light after the administration of time-spaced fluorescent (tetracycline) markers.
 |
| FIGURE 132-1 • Predominant hyperparathyroid bone disease with a high fraction of the trabecular surface covered by osteoid seams, many osteoblasts, and osteoclasts. Peritrabecular marrow fibrosis results from proliferating stromal cells that move efficiently through the osteoblastic differentiation program in an undecalcified 3-μm-thick section of iliac bone (brightfield light microscopy, modified Masson-Goldner stain, original magnification ×125). |
Low-Turnover Bone Disease, Adynamic Bone Disorder
Low-turnover uremic osteodystrophy is the other end of the spectrum of ROD. The histologic hallmark of this group is a profound decrease in bone turnover because of a low number of active remodeling sites, suppression of bone formation, and low resorption, which is not as decreased as formation. The result is a low-turnover osteopenic condition. Lining cells with few osteoclasts and osteoblasts cover the majority of trabecular bone. Bone structure is predominantly lamellar, and the extent of mineralizing surfaces is markedly reduced. Usually only a few thin, single tetracycline labels are observed. Two histologic subgroups can be identified in this type of ROD, depending on the cause of events leading to the decline in osteoblast activity: adynamic bone disorder and low-turnover osteomalacia from Al+3 intoxication osteomalacia and adynamic bone disease. With Al+3-induced adynamic uremic bone disease, the reduction in mineralization is obscured because of concomitant decreased bone formation. Adynamic uremic bone disease is characterized by few osteoid seams and few bone cells (Fig. 132-2).
Low-turnover osteomalacia is marked by an accumulation of unmineralized matrix in which a diminution in mineralization precedes or is more pronounced than the inhibition of collagen deposition. Unmineralized bone represents a sizable fraction of the trabecular bone volume. The increased lamellar osteoid volume is due to the presence of wide osteoid seams that cover a large portion of the trabecular surface (Fig. 132-3). The occasional presence of woven bone buried within the trabeculae indicates past high bone turnover. When osteoclasts are present, they are usually seen within trabecular bone or at the small fraction of the trabecular surface left without osteoid coating.
 |
| FIGURE 132-3 • Low-turnover osteomalacia. Osteoid has accumulated, and a high ratio of osteoid surface to bone surface, thick osteoid seams, and absence of active osteoblasts or osteoclasts are noted on an undecalcified 3-μm-thick section of iliac bone (brightfield light microscopy, modified Masson-Goldner stain, original magnification ×160). |
Mixed Uremic Osteodystrophy, High-Turnover Renal Osteodystrophy, and a Mineralization Defect
Mixed uremic osteodystrophy is caused primarily by hyperparathyroidism and defective mineralization with or without increased bone formation. These features may coexist in various degrees in different patients. Increased numbers of heterogeneous remodeling sites can be seen (Fig. 132-4). The number of osteoclasts is generally increased. Because active foci with numerous cells, woven osteoid seams, and peritrabecular fibrosis coexist next to lamellar sites with more reduced activity, greater production of lamellar or woven osteoid causes an accumulation of osteoid with a normal or increased thickness of osteoid seams. Whereas active mineralizing surfaces increase in woven bone with a higher mineralization rate and diffuse labeling, mineralization surfaces may be reduced in lamellar bone with a decreased mineral apposition rate.
 |
| FIGURE 132-4 • Adynamic bone disorder. No accumulation of osteoid and absence of osteoblasts and osteoclasts are seen on an undecalcified 3-μm-thick section of iliac bone (brightfield light microscopy, modified Masson-Goldner stain, original magnification ×125). |
Associated Features
Osteoporosis and Osteosclerosis
With progressive loss of renal function, cancellous bone volume may be increased along with loss of cortical bone, but this is in part due to deposition of woven immature collagen fibrils instead of lamellar fibrils. Thus, bone strength suffers despite the increase in mass detected by dual-energy x-ray absorptiometry. Patients undergoing chronic dialysis might have a loss or gain in bone volume depending on bone balance. In the case of negative bone balance, bone loss occurs in cortical and cancellous bone and is more rapid when bone turnover is high. In such cases, bone densitometry will detect osteopenia or osteoporosis. When the bone balance is positive, osteosclerosis may be observed when osteoblasts are active in depositing new bone (especially woven), thus superseding bone resorption. When bone turnover is low, however, positive phosphorus and calcium balance results in hyperphosphatemia and hypercalcemia without an increase in skeletal mineral deposition, but with stimulation of heterotopic mineralization, especially of the vasculature.
Bone Aluminum, Iron, Lanthanum, and Bisphosphonate Accumulation
These substances accumulate in bone at the mineralization front, at cement lines, or diffusely. The extent of stainable aluminum at the mineralization front correlates with histologic abnormalities in mineralization. Aluminum deposition is most severe in cases of low-turnover osteomalacia. However, it can be observed in all histologic forms of ROD. In patients in whom an increased aluminum burden develops, bone mineralization and bone turnover progressively decrease. These abnormalities are reversed with removal of the aluminum. Iron also accumulates at the mineralization front and can cause low-turnover forms of ROD similar to aluminum, although much less is known of iron than aluminum intoxication. Lanthanum has recently been added as a trace metal administered to CKD and ESKD patients. It is poorly absorbed and its levels in bone are much less than those of aluminum. Whether it will prove to have toxic effects remains unknown, but 2-year data suggest not. Lanthanum disappearance from bone deposits is slow, but not as slow as disappearance of bisphosphonate from bone deposits. Bisphosphonates are drugs used for the treatment of osteoporosis and hypercalcemia. There are increasing instances of bisphosphonate use in patients with CKD and ESKD. However, the nature of the bone remodeling abnormalities in CKD, especially with woven bone formation and mineralization defects, creates a high level of risk for skeletal deposition of a substance that once deposited may not be removed. Such a risk for long-term retention of an active drug is now being recognized with the use of bisphosphonates for osteogenesis imperfecta.
Clinical Manifestations
Patients with mild to moderate kidney insufficiency are rarely symptomatic from ROD and its skeletal pathology. However, we must consider vascular calcification a complication of ROD and the appearance of ROD as a cause of vascular stiffness. Vascular stiffness results in an increase in systolic blood pressure, widening of the pulse pressure, and an increase in pulse wave velocity in CKD. Vascular calcification is a clinically important complication of ROD that develops while the patient may be asymptomatic in the musculoskeletal system.
Symptoms of ROD related to the skeleton appear in patients with advanced kidney failure. Clinical manifestations are, however, preceded by an abnormal biochemical profile that should alert the physician and prompt steps to prevent more severe complications. When symptoms related to the skeleton occur, they are usually insidious, subtle, nonspecific, and slowly progressive.
Heterotopic Mineralization, Calciphylaxis, and Tumoral Calcinosis
Vascular calcification is common in patients with ESKD and causes left ventricular hypertrophy, congestive heart failure, and coronary ischemia. The pathogenesis of vascular calcification in CKD is complex, but it involves activation of an osteogenic program in cells of the neointima around atherosclerotic plaques and the tunica media. Diffuse calcification of the tunica media is referred to as Mönckeberg's sclerosis. CKD is the most common cause of Mönckeberg's sclerosis, especially when it complicates diabetes mellitus (Chapter 248). All forms of ROD are associated with vascular calcification, but especially important is the association between low-turnover osteodystrophy and vascular calcification. Here, the decrease in skeletal osteoblast function is associated with osteoblastic differentiation of cells in the vasculature. Furthermore, signals derived from the skeleton are direct causes of the vascular mineralization. One such signal is hyperphosphatemia.
Heterotopic tissue calcification may occur in the eyes and be manifested as band keratopathy in the sclerae or induce an inflammatory response in the conjunctiva known as red eye syndrome. These types of calcification are generally associated with hyperparathyroidism or increased calcium phosphate product. Calcium deposits are also found in the lungs and lead to restrictive lung disease. Deposits in the myocardium might cause arrhythmias, annular calcifications, or myocardial dysfunction. Most soft tissue calcifications are attributed to secondary hyperparathyroidism or to the increased calcium phosphate product associated with it. However, they have also been described in patients with adynamic bone disease. This diversity could be explained by increased calcium or phosphate release (or both) from bone in patients with severe hyperparathyroidism and an inability to maintain normal mineral accretion in patients with adynamic bone disease.
The syndrome of calciphylaxis is characterized by vascular calcification in the tunica media of peripheral arteries. These calcifications induce painful violaceous skin lesions that progress to ischemic necrosis. This syndrome has been linked to serious complications and often death. Calciphylaxis has been associated with high serum calcium phosphate product and severe secondary hyperparathyroidism. However, it can also be seen in patients with normal or mildly elevated serum phosphate or PTH levels. The pathogenesis of calciphylaxis is probably multifactorial because hyperparathyroidism, high calcium phosphate product, steroid therapy, vitamin D therapy, iron overload, aluminum toxicity, and protein C deficiency have all been implicated.
Tumoral calcinosis is a form of soft tissue calcification that usually involves the periarticular tissues. Calcium deposits may grow to enormous size and interfere with the function of adjacent joints and organs. Although this type of calcification is generally associated with high calcium phosphate product, its exact pathogenesis is poorly understood. It may also be associated with certain ill-defined intrinsic factors. Similar to soft tissue calcification, it is observed with severe hyperparathyroidism and low-turnover bone disease.
Bone Pain, Fractures, and Skeletal Deformities
Bone pain is usually vague, ill defined, and deep-seated. It may be diffuse or localized in the lower part of the back, hips, knees, or legs. Weight bearing and changes in position commonly aggravate it. Bone pain may progress slowly to the degree that patients are completely incapacitated. Bone pain in patients with ESKD does not usually cause physical signs; however, local tenderness may be apparent with pressure. Occasionally, pain can occur suddenly at one joint of the lower extremities and mimic acute arthritis or periarthritis not relieved by heat or massage. A sharp chest pain may indicate a rib fracture. Spontaneous fractures or fractures after minimal trauma may also occur in the vertebrae (crush fractures) and tubular bones.
Bone pain and bone fractures can be observed in all patients with ESKD independent of the underlying histologic bone disease, especially when osteoporosis is present. However, low-turnover osteomalacia and aluminum-related bone disease are associated with the most severe bone pain and the highest incidence of fractures and incapacity.
Skeletal deformities can be observed in children and adults. Most children with ESKD have growth retardation, and bone deformities may develop from vitamin D deficiency (rickets) or secondary hyperparathyroidism. In rickets, bowing of the long bones is seen, especially the tibia and femur, along with typical genu valgum that becomes more severe with adolescence. Long-standing secondary hyperparathyroidism in children may be responsible for slipped epiphyses secondary to impaired transformation of growth cartilage into regular metaphyseal spongiosa. This complication most commonly affects the hips, becomes obvious in preadolescence, and causes limping but is usually painless. When the radius and ulna are involved, ulnar deviation of the hands and local swelling may occur. In adults, skeletal deformities can be observed in those with severe osteomalacia or osteoporosis and include lumbar scoliosis, thoracic kyphosis, and recurrent rib fractures.
Diagnosis
ROD is characterized pathologically, and the only unequivocal tool for exact diagnosis is bone biopsy. Histologic examination of mineralized bone after tetracycline double labeling determines the precise level of bone formation, mineralization, bone resorption, and bone turnover. Special stains determine Al, Fe, or La deposition, if present. The results of bone biopsy serve as the basis for appropriate use of tailored therapeutic regimens.
In the absence of bone biopsy, the physician needs to estimate the level of bone turnover, the presence of osteomalacia (Chapter 265), and the possibility of bone toxicity from deposition of an unwanted ion. Abnormalities in serum calcium, phosphorus, and alkaline phosphatase levels indicate severe ROD but are not helpful when used alone to indicate bone turnover or osteomalacia. Hypercalcemia may be observed in cases of severe hyperparathyroidism or adynamic bone disease, especially with vitamin D therapy. Hyperphosphatemia is an indication of noncompliance with phosphate binders or severe hyperparathyroidism secondary to increased release of phosphorus from bone. High serum levels of alkaline phosphatase may be observed in both osteomalacia and predominant hyperparathyroidism.
Serum PTH levels are better indicators of bone turnover. However, the abnormalities in PTH metabolism that accompany CKD have complicated PTH measurements. The “intact” hormone assay currently used widely actually measures both PTH(1-84) and amino-terminal–truncated fragments because the epitope recognized by the amino-terminal antibody detects a sequence beginning with amino acid 13. Because the chief cells in CKD variably secrete fragments such as 7-84, the intact assay may measure an inhibitory peptide of PTH and significantly overestimate biologic PTH activity. However, careful assessment of the predictive value of serum PTH levels for bone turnover shows that all patients with serum PTH levels within or below the normal range (<65 pg/mL) have low bone turnover. Serum PTH levels above 500 pg/mL are 100% and 95.5% specific for high bone turnover in patients maintained on hemodialysis and peritoneal dialysis, respectively. For the majority of dialyzed patients, that is, those with serum PTH levels between 65 and 500 pg/mL, bone turnover unfortunately cannot be predicted accurately by the “intact” PTH assay. In addition to serum PTH values, certain risk factors for low bone turnover have been isolated and include peritoneal dialysis, diabetes, advanced age, high calcium content in the dialysate, high doses of phosphate binders, aggressive vitamin D therapy, or previous parathyroidectomy. However, in individual patients, discrepancies between risk factors, PTH levels, and bone turnover are frequent; this situation calls for bone biopsy. PTH assays that measure PTH(1-84) exclusively confirm that the “intact” PTH assay detects not only PTH(1-84) but also large C-PTH fragments. These large fragments antagonize the effects of PTH(1-84) on serum calcium and bone turnover. However, the value of these PTH assays has not been determined in CKD, and routine implementation of these assays has not been achieved.
Skeletal radiographic abnormalities are seen when ROD is advanced and include erosive cortical defects in the skull (pepper pot skull), acro-osteolysis of the clavicula, and erosion of the terminal finger phalanges. A rugger-jersey appearance of the spine and a ground-glass appearance of the skull, ribs, pelvis, and metaphyses of tubular bones reflect advanced cancellous changes. In severe hyperparathyroid bone disease, pseudocysts or brown tumors may be observed. Radiographs underestimate the extent of ROD. Signs of increased bone resorption may be seen on radiographs and reflect past resorption activity, which may have been succeeded by the accumulation of osteoid. Because osteoid is radiolucent, the superimposed osteomalacia will be missed by radiographic examination. Looser's zones, or straight bands of radiolucency abutting the cortex and running perpendicular to the long axis of bone, are of relatively low sensitivity and low specificity for the diagnosis of osteomalacia.
Aluminum accumulation may be seen at any level of bone turnover or any serum PTH level. Although correlations exist between random serum aluminum levels and the extent of stainable aluminum in bone, no threshold value allows a clear-cut distinction between patients with and patients without aluminum-related bone disease. The deferoxamine infusion test improves the sensitivity of random serum aluminum levels. An increase in serum aluminum levels of greater than 200 μg/L 48 hours after a standardized infusion constitutes a positive result. This test, though improving the sensitivity of predicting aluminum-related bone disease, does not add specificity. Having both a positive deferoxamine test and a PTH level less than 200 pg/mL will make the diagnosis of aluminum-related bone disease with almost absolute certainty. However, the combination test greatly reduces the sensitivity.
Prevention and Treatment
Medical Therapy
Therapeutic intervention should begin before advanced ROD develops. By the time of institution of dialysis, patients should be receiving therapy for ROD. Avoiding deviations in serum phosphorus and calcium levels from normal can optimize PTH levels.
Control of Serum Phosphorus and Calcium
The available dialytic methods are inefficient in removing phosphorus because of compartmentalization and slow efflux of phosphorus from the exchangeable space. Hemodialysis for 4 hours three times a week removes approximately 3 g of phosphorus per week in the face of roughly 7 g of intake. Nocturnal dialysis for longer periods and daily dialysis are effective in maintaining normal phosphorus levels. Dietary phosphate restriction in ESKD is limited because of nutritional needs. Phosphate is present in most protein-containing food products. The current recommendations for protein intake in dialyzed patients are at least 1.2 g/kg/day (hemodialysis) and 1.3 g/kg/day (peritoneal dialysis), which provide a minimum of 1 g of phosphorus per day. Therefore, the addition of phosphate binders is needed in most patients. Currently used phosphate binders are calcium carbonate, calcium acetate, sevelamer, lanthanum carbonate, and others to a minor degree. Phosphate binders should be taken with meals and in proportion to the size of the meal. Calcium citrate should be avoided because it promotes intestinal aluminum absorption. Aluminum-containing phosphate binders, though more potent than calcium salts, should not be used because of the risk for aluminum-related bone disease. Calcium-containing phosphate binders are effective but increase serum calcium levels and sometimes cause hypercalcemia and an increase in calcium phosphate product. This may suppress bone formation and stimulate vascular calcification. A non–calcium-containing phosphate binder, sevelamer hydrochloride (Renagel), is an alternative to calcium salts. This drug has been shown to be associated with less progression of coronary and aortic calcification than occurs with calcium-containing phosphate binders. Tolerability and cost are limiting factors of sevelamer therapy. Lanthanum carbonate is a newer potent and well-tolerated phosphate binder. It does not appear to accumulate to toxic levels in bone as aluminum does, but only longer-term experience with lanthanum carbonate will determine its role as a therapeutic agent. Ferric citrate is available, but it may share the effects of Al+3 on bone remodeling.
Hypocalcemia in CKD may be corrected by control of serum phosphorus and vitamin D treatment. Calcium salt administration between meals as a Ca supplement should be limited to patients with symptomatic hypocalcemia.
Use of Vitamin D and Its Metabolites
Replacement of the deficient hormone calcitriol with active vitamin D analogues may begin in patients with CKD and is routine in those with ESKD. Vitamin D analogues are effective in suppressing secondary hyperparathyroidism. In moderate hyperparathyroidism with or without mineralization defects, oral administration of calcitriol, doxercalciferol, or paricalcitol usually decreases serum PTH levels and improves mineralzation. It is advisable to start with low doses and increase the daily dose in steps to adjust PTH levels to target values after 2 weeks of therapy. Episodes of hypercalcemia may occur and can be circumvented by decreasing oral calcium salts if serum phosphate levels permit or by lowering the dialysate calcium content. Despite these measures, however, hypercalcemia may persist. Intravenous treatment regimens using high doses of one of the vitamin D analogs two or three times per week have become predominant. These measures are effective, but the positive response is clearly reduced if the parathyroid glands undergo monoclonal growth transformation and become refractory to the action of calcitriol. The vitamin D analogues 19-nor-1α,25-dihydroxyvitamin D2 (Zemplar) and doxercalciferol (Hectorol) have been introduced for the control of secondary hyperparathyroidism, and their use has largely replaced calcitriol. They have somewhat different profiles of activity at the various tissues affected by calcitriol.
Because expression of the VDR and 25-OH cholecalciferol 1α-hydroxylase is more widespread than initially thought, deficiencies in the precursor vitamin D, 25-hydroxyvitamin D, should be ruled out or corrected if found.
Use of Calcimimetics
Recently, calcimimetic agents have been introduced for the control of PTH levels in CKD and ESKD. This new class of therapeutic agents represents allosteric modulators of the calcium-sensing receptor and allow for suppression of PTH synthesis and secretion while simultaneously lowering serum calcium and phosphorus levels. Therapy with cinacalcet appears to increase the proportion of subjects achieving K/DOQI PTH and Ca × PO4 targets. However, it remains to be seen whether this will translate into improvement in bone health or cardiovascular outcomes.
Removal of Aluminum
Any therapeutic maneuver that lowers plasma aluminum levels and creates a concentration gradient across the bone–extracellular fluid membrane will be able to move aluminum from bone to blood. Because aluminum is 80% protein bound, only 20% of total aluminum can be removed by ultrafiltration. Elimination of aluminum from bone through normal turnover and by completely withdrawing aluminum sources is very slow and may take years. However, aluminum removal is greatly enhanced with use of the chelator agent deferoxamine. Deferoxamine increases the complex bound fraction of aluminum and facilitates its removal through dialysis. The association between deferoxamine therapy and infection has been a subject of controversy. Numerous case reports of bacteremia and mucormycosis during deferoxamine therapy have been published, but a large survey did not confirm that deferoxamine increases the risk for bacteremia in dialysis patients. The relationship between deferoxamine therapy and mucormycosis represents a very serious complication. Therefore, unequivocal documentation of aluminum overload is required before deferoxamine therapy is begun.
Surgical Therapy
Parathyroidectomy
Despite treatment, overt secondary hyperparathyroidism develops in some patients and may necessitate parathyroidectomy. Indications for parathyroidectomy include (1) persistent hypercalcemia despite no vitamin D treatment and modulation of the dialysate calcium concentration, (2) persistent hyperphosphatemia and a high calcium phosphate product despite aggressive dietary counseling and compliance with prescriptions, (3) progressive and symptomatic soft tissue calcification with high bone turnover (including calciphylaxis), (4) severe progressive and symptomatic hyperparathyroidism when a rapid reduction in PTH is required and vitamin D pulse therapy has failed, and (5) refractory pruritus. Before parathyroidectomy is performed, histologic evidence of severe hyperparathyroidism and absence of aluminum accumulation should be documented.
The most frequently used surgical approaches to parathyroidectomy are subtotal parathyroidectomy and total parathyroidectomy with parathyroid autotransplantation. Subtotal parathyroidectomy risks the possibility of inadequate reduction in parathyroid gland mass or the recurrence of hyperparathyroidism in the remaining tissue. These complications might require re-exploration of the neck, which can be difficult because of the formation of scar tissue. Marking the remaining gland with a metallic clip or a suture may facilitate re-exploration. Total parathyroidectomy with parathyroid autotransplantation in the forearm allows easy access to the residual parathyroid tissue if necessary. However, migration of the transplanted cells into the venous circulation and the muscles of the forearm has been reported. The success of both techniques relies on the expertise and experience of the surgeon.
Patients undergoing parathyroidectomy require careful follow-up and meticulous management. Postoperative hypocalcemia should be anticipated and treated with oral and intravenous calcium. The use of calcitriol may minimize the need for large doses of calcium salts; however, its use may interfere with successful function of the transplanted gland. A reasonable approach would be the use of intravenous calcitriol administered at the end of each dialysis treatment for two to three treatments before parathyroidectomy, followed by the lowest dose of oral calcitriol needed.
Treatment of Adynamic Bone Disease
At the present time, adynamic bone disease should be managed by measures to increase PTH levels and increase remodeling. Although no specific treatment is available, effective measures include a reduction in calcium-containing phosphate binders or the dialysate calcium content (or both). Discontinuation of vitamin D analogues and calcimimetics may be necessary. Preventive measures should be carefully considered because of the morbidity of vascular calcification and the threat to the hematopoietic stem cell associated with this form of ROD.
|
|