Avoiding a Pain in the Neck: Dialysis-Related Amyloidosis

The longer you are on dialysis, the greater the odds that you may develop dialysis-related amyloidosis (DRA). What is DRA? Beta-2 microglobulin ( B₂M ), a protein, forms into long strands. These strands, or fibrils, are called amyloid. They build up in joints, bones, and soft tissues—where they can cause pain and damage. Better equipment makes DRA less likely today than in the past. And, there are steps you can take now to reduce your risk down the road.

Causes of DRA

It is normal to have B₂M in your body. In fact, B₂M is found on the surface of most of your cells. Healthy kidneys remove excess B₂M that builds up when your cells break down. ¹ Failed kidneys can't remove B₂M , so you have to rely on dialysis or transplant.

DRA occurs when B₂M forms into fibrils. A number of factors can trigger the forming of fibrils, like:

• Heparin—a blood thinner used in most hemodialysis (HD) ²
• Reuse of HD dialyzers with the chemical Renalin ³
• Blood that is slightly more acidic than normal ⁴ (more common for patients on dialysis)
• Inflammation ⁵
• Not removing enough B₂M with dialysis ⁵

Another key reason that amyloid fibrils form is oxidative stress. This is damage that occurs when cells react with oxygen. It's quite a bit like rust! This type of stress on your body is more likely if you:

• Have low levels of vitamin C, E, or selenium ⁶ (NOTE: Take vitamins only with your doctor's okay—some can build up to toxic levels when your kidneys can't remove them)
• Are older ⁶
• Have diabetes ⁶
• Have a lot of inflammation ⁶
• Don't get enough dialysis ⁶

One type of oxidative stress is due to advanced glycation end products, or AGEs. AGEs form when sugar reacts with protein or fat. You can see AGEs in "browned" foods like coffee beans, roasted meats, and baked goods. (Your body absorbs about 30% of the AGEs in foods you eat.⁷) AGEs also form in your body, and in higher levels if you have diabetes. AGEs damage blood vessels and nerves.

It takes many years—often 10 to 20—for amyloid to cause symptoms in people on dialysis. For reasons doctors don't yet know, B₂M fibrils tend to attack joints and bones. In the spine, the problem first appears in the discs of the neck, then in the middle discs, and last in the lower back. ⁸

Joints that move more may be more prone to amyloid. ⁸ This may be why hands and wrists are so often affected. Carpal tunnel syndrome occurs when nerves for the hand are squashed in a too-small tunnel of bone. This leads to pain and numbness. One study found more carpal tunnel syndrome in access than non-access arms. ⁹ Another found that 2/3 of carpal tunnel syndrome in people on dialysis was due to amyloid. ¹⁰ "Trigger finger", a problem where a thumb or finger can get stuck in a bent position, can also be due to amyloid.

Bones are a second major target for amyloid damage. At any given moment, tiny spots of your bones are being remodeled—broken down and rebuilt. Osteoclast cells break down old bone so it can be fixed and made stronger. In mice, B₂M brought more osteoclast cells to bone to break them down. ¹¹ Amyloid can cause painful bone cysts and fractures. Like wrists, shoulders can be affected, too. ¹²

Rarely, amyloid can harm soft tissues. Researchers have found amyloid in the heart, ^13,14 the buttocks, ¹⁵ the gut (causing pain and bleeding), ^16,17 and even the tongue. In the tongue, amyloid can affect both taste and speech. ¹⁸

Prevention and treatment of DRA

It's best not to get DRA. How can you avoid it? The causes give you some clues. While none of us can avoid aging, you can:

• Ask your doctor about antioxidants that would be safe for you.
• Avoid inflammation. If you have a catheter for HD access, a fistula would reduce your risk. Ultrapure HD fluid—which has fewer germs—reduces blood levels of B₂M , perhaps because it causes less inflammation. ¹⁹
• If you do HD with reuse, make sure Renalin is not used.
• Keep your blood sugar in control if you have diabetes. Side effects are more likely if your sugars run high.
• On a PD cycler, see if you can use icodextrin for the night-time exchange. ²⁰ (Regular PD fluid has a higher level of AGEs. Sugar in the fluid browns, or caramelizes, during manufacturing.)
• If you do HD, get as much treatment as you can. High-flux dialyzers remove more B₂M than low-flux ones. ²¹ This is one reason why fewer people on HD have amyloid today than in the past. Short daily HD six times per week removed 56% more AGEs than standard HD. ²² Six nightly HD treatments removed 4.6 times more B₂M than standard HD. ²³

If you have DRA, the symptoms can be treated. Surgery can help ease carpal tunnel syndrome and trigger finger. A kidney transplant can help reduce pain quite quickly—in as little as a week, though the bone cysts and damage don't go away. ²⁴ In the future, other treatment options may come forward. Much of the research done on DRA is from Japan. There, people on HD can have their blood passed through Lixelle, a column that removes B₂M . Studies have found that Lixelle helps joint stiffness and pain, and prevents bone cysts compared to standard HD. ²⁵

Lasers have also been used to break up B₂M fibrils. This may one day help to keep fibrils from forming and to treat them once they have formed. ²⁶ This research was also done in Japan.

Finally, a new study from Greece uses magnets to reduce B₂M levels in the blood of people on HD. Before an HD treatment, magnet nanoparticles are given by IV. A magnetic dialyzer is used to pull the tiny magnets back out of the blood. Since B₂M is attracted to the magnets, the HD treatment pulls B₂M out, too. ²⁷

Conclusion

DRA can cause pain and damage to bones, joints, and tissues. But advances in HD have made the problem less common. You can take steps today to reduce your risk of DRA later.

References:

1. Floege J, Wilks MF, Soose M, Kotzerke J, Shaldon S, Koch KM. Renal elimination of beta-2 microglobulin and myoglobulin in paitents with normal and impaired renal function. Nephron. 1990, 55(4):361-7.
2. Relini A, De Stefano S, Torrassa S, Cavelleri O, Rolandi R, Gliozzi A, Georgetti S, Raimondi S, Marchese L, Verga L, Rossi A, Stoppini M, Bellotti V. Heparin strongly enhances the formation of beta-2-microglobulin amyloid fibrils in the presence of type I collagen. J Biol Chem. 2008 Feb 22;283(8):4912-20.
3. Castro R, Morgado T. Beta(2)-microglobulin clearance decreases with Renalin reuse. Nephron. 2002 Mar;90(3):347-8.
4. Corlin DB, Johnsen CK, Nissen MH, Heegaard NH. A beta2-microglobulin cleavage variant fibrillates at near-physiological pH. Biochem Biophys Res Commun. 2009 Apr 3;381(2):187-91
5. Ohashi K. Pathogenesis of beta2-microglobulin amyloidosis. Pathol Int. 2001 Jan;51(1):1-10.
6. Locatelli F, Canaud B, Eckardt KU, Stenvinkel P, Wanner C, Zoccali C. Oxidative stress in end-stage renal disease: an emerging threat to patient outcome. Nephrol Dial Transplant. 2003 Jul;18(7):1272-80.
7. What Are Advanced Glycation End Products? (Accessed 12/21/2009.)
8. Ohashi K, Hara M, Kawai R, Ogura Y, Honda K, Nihei H, Mimura N. Cervical discs are most susceptible to beta 2-microglobulin amyloid deposition in the vertebral column. Kidney Int. 1992 Jun;41(6):1646-52.
9. Namazi H, Majd Z. Carpal tunnel syndrome in patients who are receiving renal dialysis. Arch Orthop Trauma Surg. 2007 Oct;127(8):725-8.
10. Chary-Valckenaere I, Kessler M, Mainard D, Schertz L, Chanliau J, Champignuelle J, Pourel J, Gaucher A, Netter P. Amyloid and non-amyloid carpal tunnel syndrome in patients receiving chronic renal dialysis. J Rheumatol. 1998; 25(6):1164-70.
11. Menaa C, Esser E, Sprague SM. Beta2-microglobulin stimulates osteoclast formation. Kidney Int. 2008 Jun;73(11):1275-81.
12. Konishiike T, Hashizume H, Nishida K, Inoue H, Nagoshi M. Shoulder pain in long-term hemodialysis patients. A clinical study of 166 patients. J Bone Joint Surg Br. 1997 Jul;78(4):601-5.
13. Takayama F, Miyzaki S, Morita T, Hirasawa Y, Niwa T. Dialysis-related amyloidosis of the heart in long-term hemodialysis patients. Kidney Int Suppl. 2001 Feb;78:S172-6.
14. Kawano M, Muramoto H, Yamada M, Minamoto M, Araki H, Koni I, Mabuchi H, Nonomura A. Fatal cardiac beta2-microglobulin amyloidosis in patients on long-term hemodialysis. Am J Kidney Dis. 1998 Mar;31(3):E4.
15. Montagna G, Raimondi S, Moro G, Uggetti C, Relini A, Magrini U, Esposito G, Giorgetti S, Congi L, Mosconi M, Galli G, Villa G, Segagni S, Donadei S, Obici L, Merlini G, Stoppini M, Bellotti V. Clinical, radiological, and biochemical features of a bilateral buttock amyloidoma emerging after 27 years of hemodialysis. 2009 Jul 15:1-7. [Epub ahead of print.]
16. Jimenez RE, Price DA, Pinkus GS, Owen WF Jr. Lazarus JM, Kay J, Turner JR. Development of gastrointestinal beta2-microglobulin amyloidosis correlates with time on dialysis. Am J Surg Pathol. 1998 Jun;22(6):729-35.
17. Takahashi S, Morita T, Koda Y, Murayama H, Hirasawa Y. Gastrointestinal involvement of dialysis-related amyloidosis. Clin Nephrol. 1988 Sep;30(3):168-71.
18. Matsuo K, Nakamoto M, Yasunaga C, Goya T, Sugimachi K. Dialysis-related amyloidosis of the tongue in long-term hemodialysis patients. Kidney Int. 1997 Sep;52(3):832-8.
19. Furuya R, Kumagai H, Takahashi M, Sano K, Hishida A. Ultrapure dialysate reduces plasma levels of beta2-microglobulin and pentosidine in hemodialysis patients. Blood Purif. 2005;23(4):311-6.
20. Tomo T. Peritoneal dialysis solutions low in glucose degredation products—evidence for clinical benefits. Perit Dial Int. 2008 Jun;28 Suppl S:S123-7.
21. Kuchle C, Fricke H, Held E, Schiffl H. High-flux hemodialysis postpones clinical manifestations of dialysis-related amyloidosis. Am J Nephrol. 1996;16(6):484-8.
22. Floridi A, Antolini F, Galli F, Fagugli RM, Floridi E, Buoncristiani U. Daily haemodialysis improves indices of protein glycation. Nephrol Dial Transplant. 2002 May;17(5):871-8.
23. Raj DS, Ouwendyk M, Francoeur R, Pierratos A. Beta(2)-microglobulin kinetics in nocturnal haemodialysis. Nephrol Dial Transplant. 2000 Jan;15(1):58-64.
24. Morad G, Argiles A. Renal transplantation relieves the symptoms but does not reverse beta 2-microglobulin amyloidosis. J Am Soc Nephrol. 1996 May;7(5):798-804.
25. Gejyo F, Kawaguchi Y, Hara S, Nakazawa R, Azuma N, Ogawa H, Koda Y, Suzuki M, Kaneda H, Kishimoto H, Oda M, Ei K, Miyazaki R, Maruyama H, Arakawa M, Hara M. Arresting dialysis-related amyloidosis: a prospective multicenter controlled trial of direct hemoperfusion with a beta2-microglobulin adsorption column. Artif Organs. 2004 Apr;28(4):371-80.
26. Ozawa D, Yagi H, Ban T, Kameda A, Kawakami T, Naiki H, Goto Y. Destruction of amyloid fibrils of a beta2-microglobulin fragment by laser beam irradiation. J Biol Chem. 2009 Jan 9;284(2):1009-17.
27. Stamopoulos D, Bouziotis P, Benaki D, Zirogiannis PN, Kotsovassilis K, Belessi V, Dalagamas V, Papadapoulos K. Nanobiotechnology for the prevention of dialysis-related amyloidosis. Ther Apher Dial. 2009 Feb;13(1):34-41.