Hemodialysis-related Amyloidosis Research Articles

Magnetic resonance imaging classification of haemodialysis-related amyloidosis of the shoulder: risk factors and arthroscopic treatment.

This study proposed new magnetic resonance imaging (MRI) of haemodialysis shoulders (HDS) focusing on the changes of the rotator cuff, and rotator interval and risk factors for the development of HDS were examined. Eighty-five shoulders in 72 patients with a chief complaint of shoulder pain during haemodialysis and at least 10years of haemodialysis were included. They were classified into 5 groups based on the thickness of the rotator cuff and conditions of rotator interval. Clinical and radiological findings in each grade were examined, and risk factors for the development of HDS were evaluated. Arthroscopic surgeries were performed on 22 shoulders in 20 patients, and arthroscopic findings were also evaluated. Positive correlations for the development of HDS were observed in duration of haemodialysis, positive hepatitis C virus (HCV) infection, and previous haemodialysis-related orthopaedic surgery (P<0.001, respectively). Strong correlations were observed between positive HCV and the progression of HDS (odds ratio 24.8, 95% confidence interval 5.7-107.6). Arthroscopically, progression of the surrounding soft tissue degeneration was observed, and operative times were lengthened depending on the progression of MRI grading. A new MRI classification of HDS which may be helpful when considering arthroscopic surgeries has been proposed. Positive HCV infection was strongly associated with the progression of HDS on MRI. Conditions of the rotator interval and the rotator cuff based on the MRI classification should be examined when treating HDS patients. III.

Characteristics of dialysis-related amyloidosis in patients on haemodialysis therapy for more than 30 years

Dialysis-related amyloidosis is one of the chronic the complications of haemodialysis. We conducted an investigation of dialysis-associated amyloidosis in extremely long-term survivors. Twenty-one patients on haemodialysis for more than 30 years ('30+' group) and 13 patients on haemodialysis for 20-30 years ('20-30' group) at Sangenjaya Hospital were enrolled in this study. The frequencies of operations for conditions related to haemodialysis-related amyloidosis were examined. The mean age at the start of haemodialysis was younger in the '30+' group (29.1 +/- 7.3 years) than in the '20-30' group (40.5 +/- 8.2 years, P = 0.0003). Eighteen (85.7%) patients had undergone surgery for CTS, six (28.6%) had undergone surgery for trigger finger and six (28.6%) had undergone surgery for cervical destructive spondyloarthropathy (DSA) at 30 years after the start of haemodialysis therapy. Patients who were over the age of 30 years at the start of dialysis therapy more frequently underwent CTS operations (100%) than those who were under 30 years of age at the start of dialysis (76.9%; P = 0.025) in the '30+' group at 30 years after the start of haemodialysis. The frequencies of operations for CTS did not differ significantly between the '20-30' group and the '30+' group. Haemodialysis-associated amyloidosis was common in extremely long-term survivors. Even though the mean age at the start of haemodialysis was younger in the '30+' group than in the '20-30' group, the frequency of operations for CTS did not differ. This may be attributable to the recent advances in haemodialysis technologies.

Organic solvent mediated self‐association of an amyloid forming peptide from β2‐microglobulin: An atomic force microscopy study

Human beta(2)-microglobulin (beta(2)m) forms amyloid fibrils in hemodialysis related amyloidosis. Peptides spanning the beta strands of beta(2)m have been shown to form amyloid fibrils in isolation. We have studied the self-association of a 13-residue peptide Ac-DWSFYLLYYTEFT-am (Pbeta(2)m) spanning one of the beta-strands of human beta(2)-microglobulin when dissolved in various organic solvents such as methanol (MeOH), trifluoroethanol (TFE), hexafluoroisopropanol (HFIP), and dimethylsulfoxide. We have observed that Pbeta(2)m forms amyloid fibrils when diluted from organic solvents into aqueous buffer at pH 7.0 as judged by increase in thioflavin T fluorescence. Fibril formation was observed to depend on the solvents in which peptide stock solutions were prepared. Circular dichroism spectra indicated propensity for helical conformation in MeOH, TFE, and HFIP. In buffer, beta-structure was observed irrespective of the solvent in which the peptide stock solutions were prepared. Atomic force microscopy images obtained by drying the peptide on mica from organic solvents indicated the ability of Pbeta(2)m to self-associate to form nonfibrillar structures. Morphology of the structures was dependent on the solvent in which the peptide was dissolved. Peptides that have the ability to self-associate such as amyloid-forming peptides would be attractive candidates for the generation of self-assembled structures with varying morphologies by appropriate choice of surfaces and solvents for dissolution.

A case of almost-exclusively atria-dominant cardiac amyloidosis related with hemodialysis

We report a case of a 68-year-old man who had dialysis-related amyloidosis. The patient underwent neck surgery due to spondyloarthritis. Unfortunately he died after the surgery in sepsis. The preoperative routine echocardiography didn't suggest cardiac involvement of amyloidosis. However, the pathological findings in autopsy revealed severe amyloid depositions of both atria in contrast to the quite mild involvement of ventricles. We have experienced that the cardiac involvement of dialysis-related amyloidosis may be confined to atria almost sparing ventricles. Therefore, in patients with hemodialysis-related amyloidosis, even if echocardiogram doesn't suggest any ventricular amyloidosis, physicians should consider the possibility of atrial amyloidosis and should check the detail of atrial findings. If the A wave in the mitral filling pattern seems small or absent, physicians have to proceed transesophageal echocardiogram to detect intra atrial thrombus and consider anti-coagulation therapy to prevent thromboembolic complications of atrial amyloidosis.

Gastrointestinal β2microglobulin amyloidosis in hemodialysis patients: biochemical analysis of amyloid proteins in small formalin-fixed paraffin-embedded tissue specimens

We present here a first report on the biochemical analysis of intestinal amyloid deposits found in two cases of hemodialysis-related amyloidosis. A new microtechnique was applied for extraction and immunochemical/chemical characterization of amyloid proteins in small amounts of fixed tissue, thus allowing precise identification of β2microglobulin amyloid (Aβ2M) in both cases studied. The molecular mass of the identified amyloid β2M was close to that of intact β2M (12 kDa), with no evidence of the products of proteolytic fragmentation of these molecules. The isoelectrofocusing of the purified Aβ2M demonstrated a shift to more acidic pI as compared to the normal β2M analyzed under the same experimental conditions. The obtained data suggest that the intestinal amyloid deposits in dialysis-related amyloidosis contain disease-specific β2M isoforms, which could play a role in the pathogenesis of amyloid disease. The new methodology used might be useful in obtaining precise diagnosis of amyloidosis that is necessary for appropriate therapy, and also provide new important information on the chemical structure of amyloid proteins.

Co-populated Conformational Ensembles of β2-Microglobulin Uncovered Quantitatively by Electrospray Ionization Mass Spectrometry

Ordered assembly of monomeric human beta(2)-microglobulin (beta(2)m) into amyloid fibrils is associated with the disorder hemodialysis-related amyloidosis. Previously, we have shown that under acidic conditions (pH <5.0 at 37 degrees C), wild-type beta(2)m assembles spontaneously into fibrils with different morphologies. Under these conditions, beta(2)m populates a number of different conformational states in vitro. However, this equilibrium mixture of conformationally different species is difficult to resolve using ensemble techniques such as nuclear magnetic resonance or circular dichroism. Here we use electrospray ionization mass spectrometry to resolve different species of beta(2)m populated between pH 6.0 and 2.0. We show that by linear deconvolution of the charge state distributions, the extent to which each conformational ensemble is populated throughout the pH range can be determined and quantified. Thus, at pH 3.6, conditions under which short fibrils are produced, the conformational ensemble is dominated by a charge state distribution centered on the 9+ ions. By contrast, under more acidic conditions (pH 2.6), where long straight fibrils are formed, the charge state distribution is dominated by the 10+ and 11+ ions. The data are reinforced by investigations on two variants of beta(2)m (V9A and F30A) that have reduced stability to pH denaturation and show changes in the pH dependence of the charge state distribution that correlate with the decrease in stability measured by tryptophan fluorescence. The data highlight the potential of electrospray ionization mass spectrometry to resolve and quantify complex mixtures of different conformational species, one or more of which may be important in the formation of amyloid.

β 2-microglobulin and its deamidated variant, N17D form amyloid fibrils with a range of morphologies in vitro

Amyloid fibrils formed by incubation of recombinant wild-type human β 2-microglobulin (β 2M) ab initio in vitro at low pH and high ionic strength are short and highly curved. By contrast, fibrils extracted from patients suffering from haemodialysis-related amyloidosis and those formed by seeding growth of the wild-type protein in vitro with fibrils ex vivo are longer and straighter than those previously produced ab initio in vitro. Here we explore the effect of growth conditions on morphology of β 2M fibrils formed ab initio in vitro from the wild-type protein, as well as a variant form of β 2M in which Asn17 is deamidated to Asp (N17D). We show that deamidation results in significant destabilisation of β 2M at neutral pH. Despite this, acidification is still necessary to form amyloid from the mutant protein in vitro. Interestingly, at low pH and low ionic strength long, straight fibrils of recombinant β 2M are formed in vitro. The fibrils comprise three distinct morphological types when examined using electron microscopy (EM) and atomic force microscopy (AFM) that vary in periodicity and the number of constituent protofibrils. Using kinetic experiments we suggest that the immature fibrils observed previously do not represent intermediates in the assembly of fully mature amyloid, at least under the conditions studied here.

Pathogenesis of beta2-microglobulin amyloidosis.

Hemodialysis-related amyloidosis is a relatively new form of systemic amyloidosis, with beta2-microglobulin (B2M) being identified as the major constituent protein. Most of the clinical findings are related to amyloid deposition in osseo-articular tissues. B2M amyloid deposits first appear in the cervical intervertebral discs, which are well known to be susceptible to mechanical stress. A close relationship between changes of microenvironment caused by such stress and amyloid deposition is highly suggested. In advanced cases, an inflammatory reaction composed of macrophages, multinucleated giant cells, and granulation tissue, is observed around the amyloid deposits. Purified amyloid protein is native B2M, and mutations and proteolysis are not believed to be important for its deposition. Plasma levels of B2M are elevated as much as 5-10 times because of the inability of hemodialysis equipment removal of B2M from blood plasma, the duration being very important for B2M amyloid fibrillogenesis. Heparan sulfate proteoglycans, perlecan, is increased at the same sites of amyloid deposits from the early stages. In B2M amyloidosis, an increase of heparan sulfate proteoglycans is observed in the vascular wall and synovium, but in the discs, ligaments and cartilage, there is an increase of chondroitin sulfate proteoglycans predominantly. B2M has an affinity for heparan sulfate proteoglycans, although it is weaker than that for laminin and type IV collagen. This is related to the interactions between negative charges of sulfate groups of proteoglycans and positive charges of basic amino acids in N-terminal side of B2M. Increased cytokines production in the synovium, induced by advanced glycation end products as well as elevated plasma levels, is also linked to inflammatory reactions. Increased expression of matrix metalloproteinases (MMP), especially MMP-1 and -9, is related to the destructive changes of the bone and cartilage. The decrease of plasma levels by high flux membrane and control of inflammatory reactions are very important for prevention of B2M amyloidosis.

Proteoglycans in haemodialysis-related amyloidosis.

Changes in extracellular matrices of articular tissue, intervertebral discs and systemic organs in patients with haemodialysis-related amyloidosis were investigated by immunohistochemical and biochemical examination of proteoglycans. Increased staining for chondroitin sulfate (CS) was detected in the amyloid deposits of all patients, ranging from early to advanced stages. Degenerative tissue changes around early-stage amyloid deposits in the intervertebral discs also showed positive staining for CS. Heparan sulfate (HS) was detected in amyloid deposits, especially in the synovial membrane. Biochemical analysis of connective tissues containing amyloid supported the immunohistochemical studies; CS was the major glycosaminoglycan species in these tissues, accounting for 55-81% of the total glycosaminoglycans. Although previous studies have stressed the importance of HS in amyloidogenesis, the present study showed that CS, which increased significantly in articular tissues associated with mechanical stress, also has a close relationship with amyloidogenesis.

Behavior of Beta 2-microglobulin (B2-m) serum levels in uremic patients

This study was performed in 97 hemodialysis patients (85 on HD and 12 on CAPD) to investigate the possible correlation between B2-m and hemodialysis-related amyloidosis syndromes (HRA-S); differences in B2-m and HRA behavior between patients hemodialysed with cellulose and synthetic membranes were also included in the present study. Data indicate that B2-m levels are not correlated with dialysis length or with the type of membrane used for the dialysis. On the contrary, in 16 patients with the Carpal Tunnel Syndrome, a significant correlation was found between the CTS, the dialysis length and the type of membrane (greater incidence with cellulosic membranes).

Primary amyloidosis of the sternum imaging findings

A rare case of focal primary amyloidosis is presented with CT and MR correlation. Imaging findings demonstrate an expansile, mixed sclerotic and lytic lesion in the sternum, with MR signal characteristics similar to those previously described for diffuse primary amyloidosis and hemodialysis-related amyloidosis.

透析アミロイドーシスによるぼうこう出血の１例

透析アミロイドーシスによるぼうこう出血の１例

Bone cysts and haemodialysis-related amyloidosis

Carpal tunnel syndrome and arthropathy are frequent complications of long-term haemodialysis. Both are associated with cystic lesions of bone and are related to synovioarticular deposition of a new type of amyloid derived from circulating beta 2-microglobulin. Retrospective analysis of the radiographic skeletal surveys of all 58 patients on haemodialysis for 6 or more years revealed one or more cystic bone lesions in 36% of patients. Radiographic analysis indicated that a number of these cysts were due to hyperparathyroid bone disease or joint degeneration, but a majority showed features suggesting an arthropathy of another aetiology. We present evidence that the development of these latter cysts in an individual on long-term dialysis is an indicator of the presence of synovioarticular amyloidosis of the beta 2-microglobulin type. The radiographic characteristics and development of these cysts, which we believe are due to bony infiltration from synovioarticular amyloid are described.

Amyloid proteins and amyloidoses: complexity updated.

Amyloid is a beta-pleated fibrillar protein principally constituted of light chains of immunoglobulins (kappa or lambda) in primary or myeloma-associated amyloidosis, of AA proteins in secondary amyloidosis and familial. Mediterranean fever, and of variants of prealbumin - now called transthyretin - in senile amyloidosis and in familial polyneuropathies. Other identified amyloidogenic proteins involve APUD protein derivatives (calcitonin), beta 2 microglobulin in chronic hemodialysis-related amyloidosis and beta protein in Alzheimer disease. After a short review of experimental findings and theories concerning the pathogenesis of amyloid deposition, the clinical aspects of amyloidosis are discussed stressing their great diversity. The diagnostic approach is also examined, with particular emphasis on rectal and kidney biopsy and subcutaneous adipose tissue aspirates. Finally, some comments on the treatment of amyloidosis (role of colchicine and DMSO) are made.

Polymerization of intact beta 2-microglobulin in tissue causes amyloidosis in patients on chronic hemodialysis.

Systemic amyloidosis with a predilection for bone and synovium may complicate the course of patients on long-term hemodialysis. This form of amyloidosis can be typed as distinct from other amyloid diseases by using small tissue samples obtained by bone biopsy and at postmortem. Immunoblot analysis of two-dimensional gels of partially solubilized amyloid fibrils established that tissue deposits are composed of monomers, dimers, and higher polymers of beta 2-microglobulin (beta 2m) and that amyloid P component was also present. Anti-beta 2m antiserum recognized fibrils, as shown by immunoelectron microscopy. Purified monomer isolated from dissociated fibrils yielded peptides corresponding to the entire known sequence of beta 2m. Virtually all serum beta 2m, as well as that present in tissue fluid bathing amyloid fibrils, was monomeric. Hemodialysis-related amyloidosis is an example of a deposition disease occurring in hemodialysis patients. We have shown conclusively that, in this amyloid disease, polymerization of an intact normal serum protein to a fibrillar configuration may occur without proteolysis. We propose the designation A beta 2m for this form of amyloid fibril subunit protein.