Most patients who are treated with dialysis for more than 7–10 years develop deposits of a unique amyloid protein that is derived from β2M, a normal plasma constituent. Patients present with multiple bone cysts, pathologic fractures, carpal tunnel syndrome, scapulohumeral arthritis, and spondyloarthropathy. Involvement of the musculoskeletal system with bone pain and articular symptoms makes it difficult to separate dialysis-related amyloidosis from other forms of renal osteodystrophy.
The fibrils of β2M have a molecular weight of approximately 12,000 Da and are produced by many cells, particularly those of lymphoid tissue and other cells with high rates of turnover. The protein serves to stabilize the structure of the MHC class I antigen on cell surfaces, but it is released into the circulation when the complexes are shed from the cell membrane. Approximately 180–250 mg of β2M is generated normally each day. Nearly all β2M is filtered at the glomerulus and catabolized subsequently by renal tubular epithelial cells. It accumulates in plasma, however, in patients with advanced renal failure, and levels reach values 50 times greater than normal in dialysis patients with little or no residual renal function.
Histologically, β2M amyloid fibrils have an appearance that is similar to amyloid AA, but deposits of β2M occur predominantly in bones and joints, leading to musculoskeletal manifestations. Both the slow rate of appearance and the predilection for bone and articular structures suggest that elevated serum β2M levels do not fully account for the clinical syndrome observed in patients with chronic renal failure. Increases in age-related glycosylation products, certain specific proteases, and inhibitors of other proteases have each been suggested as factors that contribute to the deposition of β2M amyloid in bone and synovial tissues. Much less often, β2M amyloid deposits occur systemically, and these may be fatal.
The clinical features of amyloid deposition rarely appear before 5 years of dialysis therapy, and the disorder is more common among patients who start regular dialysis after the age of 50 years. Carpal tunnel syndrome is the most frequent clinical feature, but shoulder pain, other arthritic complaints, and cystic bone lesions are common. Deposits of β2M are found in periarticular structures, joints, bone, and tendon sheaths. Far less commonly, the liver, spleen, rectal mucosa, or blood vessels are involved.
Skeletal manifestations include generalized arthritis, erosive arthritis, and joint effusions. Scapulohumeral involvement with shoulder pain is a common clinical presentation. Generalized arthritis can lead to pain and stiffness, decreased joint mobility, joint effusions, and deformities. Pain is characteristically worse at night or when patients sit quietly for several hours during dialysis sessions. Motion of affected joints or activity provides temporary relief. Erosive arthritis can involve the metacarpophalangeal and interphalangeal joints, shoulders, wrists, and knees, sometimes with joint effusions. The cervical spine is the most common site of destructive spondyloarthropathy.
On skeletal radiographs, bone cysts are located most commonly at the ends of long bones, particularly in the femoral head and proximal humerus, but they may also occur in the metacarpal and carpal bones. Multiple cystic lesions are common, and sequential radiographs often demonstrate cyst enlargement over time. Cysts containing deposits of β2M may resemble the brown tumors of osteitis fibrosa, but their location and the presence of multiple rather than solitary cysts suggest that amyloid deposition is responsible. Cystic changes most commonly occur at sites of tendon insertions, and pathologically these may represent “amyloidomas” that have replaced trabecular bone. Fractures sometimes occur at these sites, and hip fractures in dialysis patients commonly arise at sites of β2M deposition. Examinations of the shoulder by ultrasound are a simple noninvasive method to assess progressive tendon involvement with β2M amyloid deposits.
The fraction of patients afflicted with amyloidosis increases progressively with the duration of dialysis therapy; thus, 70–80% of adult patients treated with hemodialysis for 10 or more years will have clinical features of β2M amyloidosis. The distinction between this disorder and either severe secondary hyperparathyroidism or aluminum-related bone disease can be difficult, and thorough clinical, biochemical, and radiographic evaluations are required. Amyloidosis due to β2M accumulation can coexist with either high-turnover or low-turnover skeletal lesions of renal osteodystrophy.
The clinical management of amyloidosis among patients undergoing dialysis has proven unsatisfactory. The carpal tunnel syndrome may respond to surgical correction, but it often reoccurs. The use of highly permeable dialysis membranes can moderately lower the serum levels of β2M, but there is no evidence that this intervention alters disease progression. The appearance of certain clinical features of dialysis amyloidosis may be delayed in patients treated from the onset of renal replacement therapy with dialysis membranes composed of polyacrylonitrile (PAN) membranes as compared to those treated with conventional cellulosic dialyzers. Successful renal transplantation is followed by symptomatic relief in most patients, but there is no evidence that β2M amyloid deposits in bone or other soft tissues actually regress after renal transplantation.
Serum calcium levels often are within the lower range of normal or modestly reduced in untreated patients with renal failure. After beginning treatment with dialysis, values usually rise and they may return to normal. The magnitude of the increase in serum calcium levels is in part related to the calcium concentration utilized in dialysis solutions. In patients treated with continuous ambulatory peritoneal dialysis (CAPD) who are not receiving vitamin D sterols, serum calcium levels are often within the normal range.
After calcium-containing, phosphate-binding agents were introduced as an alternative to aluminum-containing phosphate-binding medications, hypocalcemia became a less frequent problem in patients with CKD. Indeed, normal or high serum calcium levels are not uncommon among patients undergoing dialysis even in those who are not receiving vitamin D sterols. Such findings emphasize the importance of passive, vitamin D-independent intestinal calcium transport as a determinant of net intestinal calcium absorption when sufficiently large amounts of calcium are given orally to patients with renal failure.
The development of hypercalcemia in patients undergoing regular dialysis warrants prompt and thorough investigation. Common causes include marked hyperplasia of the parathyroid glands due to severe secondary hyperparathyroidism, adynamic renal osteodystrophy, treatment with calcitriol or other active vitamin D sterols, and the administration of large oral doses of calcium. Less frequent causes are aluminum-related bone disease, immobilization, malignancy, and granulomatous disorders such as sarcoidosis or tuberculosis where there is unregulated 1,25-dihydroxyvitamin D production by monocytes in granulomatous tissue. Basal serum calcium levels are generally higher and episodes of hypercalcemia occur more often in patients with adynamic bone than in persons with other skeletal lesions of renal osteodystrophy. Because skeletal calcium uptake is limited in the adynamic lesion, calcium entering the extracellular fluid from dialysate or following intestinal absorption cannot adequately be buffered in bone, and serum calcium levels rise. Lowering the doses of calcium-containing, phosphate-binding agents and decreasing temporarily the concentration of calcium in dialysate usually correct the hypercalcemia in such cases.
When the GFR falls below 15–20% of normal, hyperphosphatemia may develop. Phosphate-binding agents and dietary phosphorus restriction are usually required to avoid overt phosphate retention. Because the efficiency of phosphorus removal is limited during hemodialysis and peritoneal dialysis procedures, such measures are needed to adequately maintain serum phosphorus levels in most patients undergoing dialysis regularly without regard to the underlying type of renal bone disease.
In advanced renal failure, serum magnesium levels rise due to diminished renal magnesium excretion. Values are normal or slightly elevated when the concentration of magnesium in dialysate is kept between 0.5 and 0.8 mEq/L. The use of magnesium-containing laxatives or antacids can abruptly raise serum magnesium levels in patients with renal failure, and these medications should generally be avoided. It is prudent to monitor serum magnesium levels regularly if and when magnesium-containing medications are used.
Serum alkaline phosphatase values are fair markers of the severity of secondary hyperparathyroidism in patients with renal failure. Osteoblasts express large amounts of one isoenzyme of alkaline phosphatase, and serum levels are elevated when osteoblastic activity and bone formation are increased. High levels generally correspond to the extent of histologic change in patients with high-turnover lesions of renal osteodystrophy, and values frequently correlate with plasma PTH levels. Serum total alkaline phosphatase measurements may also be useful for monitoring the skeletal response to treatment with vitamin D sterols in patients with osteitis fibrosa. Values that decrease progressively over several months usually indicate histologic improvement.
Plasma aluminum levels are usually markedly elevated in patients with renal failure who have ongoing exposure to aluminum-containing medications or to inadequately purified dialysate. As such, plasma aluminum levels should be monitored regularly in patients undergoing maintenance dialysis, particularly in those who continue to use aluminum-containing, phosphate-binding medications. Plasma aluminum levels do not, however, serve as a reliable indicator of the extent of aluminum retention in tissues. Serum levels fall substantially within a few months after aluminum-containing medications are discontinued despite persistent aluminum retention in tissues. For these reasons, DFO infusions are a more reliable indicator of aluminum retention in tissues and provide useful information about the extent of tissue aluminum accumulation in patients undergoing dialysis.
Plasma PTH levels differ markedly according to type of renal bone disease, but double antibody immunometric assays generally provide reliable and reproducible results in patients with advanced renal failure. Indeed, plasma PTH measurements using first-generation immunometric assays are used widely for the initial diagnosis of renal osteodystrophy and to monitor therapy. The reference range of normal for these assays is generally in the range of 10–65 pg/mL, or 1–6 pM. Plasma PTH values are more useful than other serum biochemical markers for distinguishing between patients with secondary hyperparathyroidism and those with adynamic skeletal lesions. In untreated patients and in those receiving small daily oral doses of calcitriol, bone biopsy evidence of secondary hyperparathyroidism is found when plasma PTH levels exceed 250–300 pg/mL, or 25–30 pM. In contrast, values below 150 pg/mL, or 15 pM, and particularly levels below 100 pg/mL, or 10 pM, are typical for patients with adynamic renal osteodystrophy. Plasma PTH levels in the range of 150–300 pg/mL, or 2- to 4-fold higher than the upper limit of normal, generally correspond to normal rates of bone formation as documented by bone histomorphometry.
In contrast to the findings summarized previously for patients undergoing dialysis, plasma PTH levels that exceed the upper limit of normal are often associated with overt histologic evidence of secondary hyperparathyroidism in patients with earlier stages of CKD. Guidelines different from those that apply to patients treated with dialysis are thus required for patients with less advanced renal failure.
Until recently, the first-generation immunometric PTH assays that have been used widely in clinical chemistry for the past 15–20 years were thought to detect either predominantly or exclusively full-length PTH(1–84). It is now apparent, however, that these assays cross-react with other large amino-terminally truncated PTH fragments. In contrast, recently introduced second-generation immunometric PTH assays detect PTH(1–84) exclusively. When measured by second-generation assays, plasma PTH concentrations are on average 40–45% lower than values obtained using first-generation assays both in subjects with normal renal function and in those with ESRD. Several studies indicate, however, that values obtained with each assay are highly correlated.
The proper interpretation of PTH measurements in patients with renal failure depends largely on the extent to which values reflect bone histology as documented by bone biopsy. These relationships have been established for first-generation immunometric PTH assays, but only limited information is available using second-generation assays. It remains to be determined whether second-generation immunometric PTH will serve as better predictors of bone histology in patients with CKD.