Beta 2-microglobulin associated amyloidosis (A beta 2m amyloidosis) is considered an inevitable complication of chronic hemodialysis, particularly in hemodialysis with cellulose based membranes. We performed a single center study to assess the prevalence of A beta 2m amyloidosis in 1988 versus 1996. Randomly selected patients, studied in 1988, were matched for time on hemodialysis (mean 71 months, range 3 to 207) and age (mean 51 years, range 22 to 80) with patients of the 1996 population. Compared to 1988 patients, the 1996 patients exhibited a lower prevalence of carpal tunnel syndrome (7 of 43 in 1988 vs. 1 of 43 in 1996; P < 0.001) and radiological evidence of A beta 2m amyloidosis (13 of 34 patients vs. 3 of 34 patients positive; P < 0.001; and 33 of 272 possible sites affected in 1988 vs. 7 of 272 sites in 1996 patients; P < 0.05). Compared to the 1988 population, the 1996 population exhibited significantly lower serum aluminum levels, lower average serum creatinine (but not urea) levels, more frequent therapy with erythropoietin, less home hemodialysis, longer hemodialysis time using high-flux synthetic dialysis membranes (mean of 13% vs. 6% of the total hemodialysis time in the 1988 group), and more frequent usage of reverse osmosis water plus bicarbonate buffer for dialysate preparation. We conclude that the prevalence and severity of A beta 2m amyloidosis unexpectedly decreased by about 80% in our center between 1988 and 1996. Given the relatively short times spent on high flux hemodialysis in both groups, increased beta 2-microglobulin removal is unlikely to account for this phenomenon. Rather, other factors, for example, dialysate composition and purity, may be involved.
Dialysis-related amyloidosis (DRA) is a major cause of morbidity in end-stage renal disease patients. While retention of the precursor protein beta 2-microglobulin (beta 2-m) forms the essential basis for DRA, pathogenetic concepts include: qualitative and quantitative alterations in beta 2-m metabolism; local and systemic inflammatory changes, partly related to different treatment modes; general predisposing factors such as age at the onset of dialysis treatment. Clinical and radiological signs, as well as synovial thickening on sonography, suggest the presence of DRA, but histomorphological demonstration of beta 2m-amyloid is required for definitive proof. Scintigraphic imaging of DRA represents an additional, sensitive non-invasive diagnostic tool. Successful kidney transplantation stops the progression of DRA.
Amyloid of b 2 -microglobulin (b 2 m) origin can be diagnosed using 131 I-radiolabelled-b 2 m scintigraphy in patients with uremia and hemodialysis treatment. As the tracer b 2 m is isolated from another patient, it carries the common risks, including viral infections such as Hepatitis B, C and HIV, which are associated with human plasma products.In order to exclude these risks we have produced recombinant human b 2 m (rhb 2 m) in Escherichia coli. The expression vector pASK40DLb 2 m(His) 5 contains a C-terminal (His) 5 -tag for purification via immobilized metal ion affinity chromatography (IMAC). Size exclusion chromatography on a Superose 12 column represents the second step of purification.The isolated rhb 2 mH 5 reacted in an immunochemically identical manner to native human b 2 m, and showed a single band of < 11.8 kDa in Western blot analysis and revealed a single spot in two-dimensional gel electrophoresis. Mass spectrometry analysis revealed a single peak at the expected molecular mass of 12 415.8 Da. Uniformity was further proven by crystallization and N-terminal amino-acid sequence analysis.The rhb 2 mH 5 protein was then produced under conditions that allow the intravenous use in humans. Intraveneously applied indium-111-labelled rhb 2 mH 5 was monitored in hemodialysed patients with and without known b 2 m-amyloidosis. The tracer was localized specifically to particular areas known to contain amyloid.Thus, this rhb 2 mH 5 preparation is suitable for detecting amyloid-containing organs of the b 2 m-class in vivo and fulfils the requirements of a tracer for common use. Finally, the use of indium-111 instead of iodine-131 has reduced the radioactive load and resulted in higher resolution.Keywords: amyloidosis; recombinant b 2 -microglobulin; scintigraphy; indium-111; whole-body diagnosis.Amyloidosis of b 2 -macroglobulin (b 2 m) origin is a serious disease in patients with long-standing uremia and hemodialysis treatment. It is seen to occur with increasing prevalence with the duration of dialysis, with age of the patient and with the kind of dialyzer used [1±3]. As this class of amyloidosis causes severe osteo-articular symptoms with carpal tunnel syndrome and bone erosions which lead to pathologic bone fractures, early diagnosis is needed in order to achieve a timely therapeutic intervention.As early bioptic diagnosis has not yet been established, minimal invasive scintigraphic diagnosis has been reported using 131 I-labelled b 2 m [4] which was confirmed by others [5±7]. However, the tracer b 2 m in all studies was isolated from urine or uremic ultrafiltrate of other patients. Although these selected donor patients had been carefully scrutinized for any possible transmissible disease, there still remains a risk, including viral infections such as Hepatitis B, C and HIV, inherent in all human plasma products.As such a tracer may only be applicable in a limited and strictly controlled setting, it cannot be commonly applied and its commercial distribution is not feasible due to the remaining risks. The ...
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