Treatment Of Dialysis-related Amyloidosis Research Articles

Clinical Images: β2 -Microglobulin amyloidosis.

The patient, a 55-year-old man on hemodialysis (HD) (in-center HD three times per week) for 32 years (low-flux HD for 25 years), presented with a 10-year history of progressive deformity of the hands. The patient was diagnosed with β2-microglobulin amyloidosis, or dialysis-related amyloidosis (DRA), on the basis of clinical presentation and radiographic findings. Although histological assessment remains the gold standard for DRA, the diagnosis is usually clinical in patients suspected of needing HD and relies on the combination of typical clinical features, such as carpal tunnel syndrome, camptodactyly, and characteristic radiographic findings of multiple rapidly enlarging bone cysts. The bone cysts are radiolucent lesions and frequently have thin sclerotic margins (white arrows). Amyloid deposition along the flexor tendons of the hand leads to irreducible flexion contractures of the fingers (white arrowheads). Besides DRA findings, vascular calcifications, such as arteriosclerosis (red arrows), and a calcified arteriovenous fistula anastomotic aneurysm (red arrowheads) were also present in our patient's radiography. In the past, DRA was nearly a universal finding in patients with an HD vintage of more than 10 years. Also, DRA has been described in patients undergoing peritoneal dialysis and even in patients with chronic kidney disease before the initiation of dialytic therapy. However, the epidemiology of DRA has decreased in the past 20 years because of the use of high-flux membranes that have superior β2-microglobulin clearance, ultrapurified water, and more biocompatible membranes that generate less inflammation (1). Apart from enhancing β2-microglobulin clearance by high-flux HD membranes or kidney transplantation, treatment of DRA is otherwise palliative. The most debilitating aspects of DRA are carpal tunnel syndrome and paraparesis due to epidural β2-microglobulin amyloid deposition. Moreover, DRA has been shown to predispose to pathologic fractures due to bone cysts in rare cases (2). Analgesics may help with periarticular and bone pain (3).

Beta-2 Microglobulin Amyloidosis: Past, Present, and Future.

Almost half a century has elapsed since the first description of dialysis-related amyloidosis (DRA), a disorder caused by excessive accumulation of β-2 microglobulin (B2M). Within that period, substantial advances in RRT occurred. These improvements have led to a decrease in the incidence of DRA. In many countries, DRA is considered a "disappearing act" or complication. Although the prevalence of patients living with RRT increases, not all will have access to kidney transplantation. Consequently, the number of patients requiring interventions for treatment of DRA is postulated to increase. This postulate has been borne out in Japan, where the number of patients with ESKD requiring surgery for carpal tunnel continues to increase. Clinicians treating patients with ESKD have treatment options to improve B2M clearance; however, there is a need to identify ways to translate improved B2M clearance into improved quality of life for patients undergoing long-term dialysis.

In Vitro Removal of Beta‐2‐Microglobulin From Uremic Blood With an Immunoadsorption Wall

Dialysis-related amyloidosis (DRA), caused by the accumulation of beta-2-microglobulin (β-2M), remains a major concern in long-term renal replacement therapies. For years, we have developed an immunoadsorption wall (iWall) for the removal of β-2M. In this study, we employed a new approach taking advantage of the melting of a buffer ice rod to improve the conditions associated with the manufacturing of an iWall and tested its performance with uremic serum and blood. The preliminary results reveal that the present iWalls thus prepared not only possess the superior properties of affinity and specificity but also show structural stability and acceptable hemocompatibility. We believe that this breakthrough might provide a promising path to successful treatment of DRA as well as establish a useful platform for studying removal of certain pathological toxins accumulated in the blood.

Procollagen C-proteinase enhancer-1 (PCPE-1) interacts with β 2-microglobulin (β2-m) and may help initiate β2-m amyloid fibril formation in connective tissues

Dialysis related amyloidosis (DRA) is a progressive and serious complication in patients under long-term hemodialysis and mainly leads to osteo-articular diseases. Although β 2-microglobulin (β2-m) is the major structural component of β2-m amyloid fibrils, the initiation of amyloid formation is not clearly understood. Here, we have identified procollagen C-proteinase enhancer-1 (PCPE-1) as a new interacting protein with β2-m by screening a human synovium cDNA library. The interaction of β2-m with full-length PCPE-1 was confirmed by immunoprecipitation, solid-phase binding and pull-down assays. By yeast two-hybrid analysis and pull-down assay, β2-m appeared to interact with PCPE-1 via the NTR (netrin-like) domain and not via the CUB ( C1r/C1s, Uegf and BMP-1) domain region. In synovial tissues derived from hemodialysis patients with DRA, β2-m co-localized and formed a complex with PCPE-1. β2-m did not alter the basal activity of bone morphogenetic protein-1/procollagen C-proteinase (BMP-1/PCP) nor BMP-1/PCP activity enhanced by PCPE-1. PCPE-1 did not stimulate β2-m amyloid fibril formation from monomeric β2-m in vitro under acidic and neutral conditions as revealed by thioflavin T fluorescence spectroscopy and electron microscopy. Since PCPE-1 is abundantly expressed in connective tissues rich in type I collagen, it may be involved in the initial accumulation of β2-m in selected tissues such as tendon, synovium and bone. Furthermore, since such preferential deposition of β2-m may be linked to subsequent β2-m amyloid fibril formation, the disruption of the interaction between β2-m and PCPE-1 may prevent β2-m amyloid fibril formation and therefore PCPE-1 could be a new target for the treatment of DRA.

Dialysis-related amyloidosis: pathogenesis focusing on AGE modification.

Dialysis-related amyloidosis (DRA) is a serious complication in long-term dialysis patients, and presents with carpal tunnel syndrome, cystic bone lesions, destructive spondylarthropathy, diffuse arthritis and periarthritis, systemic organ involvement, and dialysis-related spinal canal stenosis (DSCS). Recently a new concept of DSCS has been proposed that includes both destructive spondylarthropathy and myeloradiculopathy induced by extradural thickness. beta(2)-microglobulin (beta(2)M) amyloid was demonstrated to be modified with advanced glycation end products (AGEs) such as imidazolone, N(epsilon)-(carboxymethyl)lysine (CML), and pentosidine. Imidazolone is a reaction product of arginine residue in proteins with 3-deoxyglucosone (3-DG), which is markedly accumulated in uremic serum. Imidazolone is generated under nonoxidative conditions, while CML and pentosidine are formed by oxidative processes. Immunoelectron microscopy demonstrated that AGEs were localized not only in dialysis amyloid but also in nonamyloid collagenous structures, supporting the hypothesis that AGE modification of collagen might have pathogenic relevance in the deposition of beta(2)M on collagen. Serum levels of AGEs are increased in uremic patients. The dimeric form of beta(2)M in the dialysate and urine of uremic patients is more susceptible to imidazolone modification as observed in dialysis amyloid. However, the major component of dialysis amyloid is a native form of beta(2)M, while AGE-modified beta(2)M and truncated beta(2)M are the minor components. Thus I propose that 3-DG and the other dicarbonyl compounds accumulating in uremic serum promote the modification of beta(2)M with AGEs mainly after deposition of beta(2)M as amyloid. For the prevention and treatment of DRA, beta(2)M should be efficiently eliminated from circulating blood by kidney transplantation, hemodialysis, or hemodiafiltration using high-flux membranes and an adsorbent (Lixelle) column.

Lixelle adsorbent to remove inflammatory cytokines.

A beta2-microglobulin (beta2M) selective adsorbent (Lixelle) for direct hemoperfusion has been used for the treatment of hemodialysis patients with the long-term complication of dialysis related amyloidosis (DRA), but there is no significant correlation between the serum level of beta2M and the occurrence of DRA. Inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNFalpha) are related to the development of DRA. We studied the adsorptive rates of cytokines in vitro using the Lixelle adsorbent. The adsorptive rates were 98.5% for IL-1beta 98.0% for interleukin-1 receptor antagonist (IL-1RA), 82.9% for IL-6, 99.9% for IL-8, 31.2% for TNFalpha, and 46.1% for soluble TNF receptor (sTNFr), respectively. As the molecular weights of cytokines increase, the adsorptive rates decrease. The Lixelle column adsorbed beta2M and various inflammatory cytokines as well. Therefore, the removal of both beta2M and inflammatory cytokines may play an important role in the treatment of DRA.

Dialysis-related amyloidosis: importance of biocompatibility and age.

The histological prevalence of dialysis-related amyloidosis (DRA) is much greater than suspected on clinical grounds: one-third of patients are affected after less than 4 years on haemodialysis (HD) and over 90% after more than 7 years HD. Risk factors include the time on dialysis, the type of HD membrane, and the age of the patient at onset of dialysis. The protective effect of high-flux membranes such as AN69 probably results mainly from the greater clearance of beta2-microglobulin. Other potential but more controversial explanations include a protective influence on residual renal function, a lower stimulation of beta2-microglobulin synthesis or release, or a beneficial influence on advanced glycosylation end (AGE) products. The higher risk of DRA in older patients has recently been suggested to result from an age-related AGE-modification of osteoarticular collagen. The best prevention and treatment of DRA is successful renal transplantation. In patients unsuitable for transplantation, high flux membranes such as AN69 should be used from the start of dialysis. Palliative treatment includes analgesics, low dose prednisone in severe cases, and surgical treatment of complications.