Rheumatology International

, Volume 32, Issue 10, pp 3155–3162 | Cite as

Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in reactive amyloidosis associated with rheumatoid arthritis

  • Takeshi Kuroda
  • Naohito Tanabe
  • Daisuke Kobayashi
  • Yoko Wada
  • Shuichi Murakami
  • Masaaki Nakano
  • Ichiei Narita
Original Article


The kidney is a major target organ for systemic amyloidosis, resulting in proteinuria and an elevated serum creatinine level. In patients with reactive amyloidosis associated with rheumatoid arthritis, a correlation between the amount of amyloid deposits and clinical parameters is not known. The purpose of this study was to clarify the association between various factors including renal function and the area of amyloid deposition in these patients. Fifty-eight patients with an established diagnosis of reactive AA amyloidosis were studied. We retrospectively investigated the correlation between clinical data and the area occupied by amyloid in renal biopsy specimens. All the patients showed amyloid deposits in renal tissues, and the percentage of the area occupied by amyloid was <10% in 54 of them. Mesangial proliferative glomerulonephritis and membranous nephropathy were frequently combined with renal amyloidosis. For statistical analyses, the percentage of the area occupied by amyloid was transformed to a common logarithmic value (Log10 % amyloid), as the histograms showed a log-normal distribution. Log10 % amyloid was found to be correlated with age, creatinine (Cr) level, creatinine clearance (Ccr), blood urea nitrogen (BUN) level, and the estimated glomerular filtration rate (eGFR). Multiple linear regression analyses were then performed to examine the sex- and age-adjusted association between Log10 % amyloid and each of the clinical variables. Cr, Ccr, BUN, UA, CRP, and eGFR were significantly correlated with Log10 % amyloid, but urinary protein was not. There was a significant correlation between the area of amyloid deposition in renal tissue and parameters of renal function, especially Cr and Ccr. If amyloid deposition in renal tissue can be arrested or prevented, then it may be possible to maintain renal function at an acceptable level.


Rheumatoid arthritis Reactive amyloidosis Renal function Renal biopsy 



This work was supported by a grant from the Intractable Disease Division of the Ministry of Health and Welfare of Japan, and the Research Committee for Epochal Diagnosis and Treatment for Amyloidosis in Japan.

Conflict of interest

None of the authors has a conflict of interest to declare.


  1. 1.
    Young A, Koduri G, Batley M, Kulinskaya E, Gough A, Norton S et al (2007) Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischemic heart disease and in pulmonary fibrosis. Rheumatology 46:350–357PubMedCrossRefGoogle Scholar
  2. 2.
    Baecklund E, Lliadou A, Askling J, Ekbom A, Backlin C, Granath F et al (2006) Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 54:692–701PubMedCrossRefGoogle Scholar
  3. 3.
    Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE (2005) Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 52:722–732PubMedCrossRefGoogle Scholar
  4. 4.
    Watson DJ, Rhodes T, Guess HA (2003) All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK general practice research database. J Rheumatol 30:1196–1202PubMedGoogle Scholar
  5. 5.
    Gertz MA, Kyle RA (1991) Secondary systemic amyloidosis: response and survival in 64 patients. Medicine (Baltimore) 70:246–256Google Scholar
  6. 6.
    Gillmore JD, Lovat L, Persey MR, Pepys MB, Hawkins PN (2001) Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid protein. Lancet 358:24–29PubMedCrossRefGoogle Scholar
  7. 7.
    Husby G, Marhaug F, Dowton B, Sletten K, Sipe JD (1994) Serum amyloid A (SAA): biochemistry, genetics and the pathogenesis of AA amyloidosis. Amyloid 1:119–137CrossRefGoogle Scholar
  8. 8.
    Cunnane G, Whitehead AS (1999) Amyloid precursors and amyloidosis in rheumatoid arthritis. Baillieres Clin Rheumatol 13:615–628CrossRefGoogle Scholar
  9. 9.
    Kobayashi H, Tada S, Fuchigami T, Okuda Y, Takasugi K, Matsumoto T et al (1996) Secondary amyloidosis in patients with rheumatoid arthritis: diagnostic and prognostic value of gastroduodenal biopsy. Br J Rheumatol 35:44–49PubMedCrossRefGoogle Scholar
  10. 10.
    El Mansoury TM, Hazenberg BP, El Badawy SA, Ahmed AH, Bijzet J, Limburg PC et al (2002) Screening for amyloid in subcutaneous fat tissue of Egyptian patients with rheumatoid arthritis: clinical and laboratory characteristics. Ann Rheum Dis 61:42–47PubMedCrossRefGoogle Scholar
  11. 11.
    Wakhlu A, Krisnani N, Hissaria P, Aggarwal A, Misra R (2003) Prevalence of secondary amyloidosis in Asian north Indian patients with rheumatoid arthritis. J Rheumatol 30:948–951PubMedGoogle Scholar
  12. 12.
    Husby G (1985) Amyloidosis and rheumatoid arthritis. Clin Exp Rheumatol 3:173–180PubMedGoogle Scholar
  13. 13.
    Kuroda T, Tanabe N, Sakatsume M, Nozawa S, Mitsuka T, Ishikawa H et al (2002) Comparison of gastroduodenal, renal and abdominal fat biopsies for diagnosing amyloidosis in rheumatoid arthritis. Clin Rheumatol 21:123–128PubMedCrossRefGoogle Scholar
  14. 14.
    Carmona L, Gonzalez-Alvaro I, Balsa A, Angel Belmonte M, Tena X, Sanmarti R (2003) Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity. Ann Rheum Dis 62:897–900PubMedCrossRefGoogle Scholar
  15. 15.
    Misra R, Wakhlu A, Krishnani N, Hissaria P, Aggarwal A (2004) Prevalence of silent amyloidosis in rheumatoid arthritis and its clinical significance. J Rheumatol 31:1031–1034Google Scholar
  16. 16.
    Ota Z, Makino H (1990) Drug-induced nephropathy in patients with rheumatoid arthritis (in Japanese). Clin Rheumatol 3:221–227Google Scholar
  17. 17.
    Samuels B, Lee JC, Engleman EP, Hopper J (1977) Membranous nephropathy in patients with rheumatoid arthritis: relationship to gold therapy. Medicine 57:319–327Google Scholar
  18. 18.
    Bender WL, Whelton A, Beschorner WE, Darwish MO, Hall-Craggs M, Solez K (1984) Interstitial nephritis, proteinuria, and renal failure caused by nonsteroidal anti-inflammatory drugs: immunologic characterization of the inflammatory infiltrate. Am J Med 76:1006–1012PubMedCrossRefGoogle Scholar
  19. 19.
    Gertz MA, Kyle RA (1991) Secondary systemic amyloidosis: response and survival in 64 patients. Medicine 70:246–256PubMedCrossRefGoogle Scholar
  20. 20.
    Nakano M, Ueno M, Nishi S, Shimada H, Hasegawa H, Watanabe T et al (1998) Analysis of renal pathology and drug history in 158 Japanese patients with RA. Clin Nephrol 50:154–160PubMedGoogle Scholar
  21. 21.
    Helin HJ, Korpela MM, Mustonen J, Pasternack A (1995) Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arthritis Rheum 38:242–247PubMedCrossRefGoogle Scholar
  22. 22.
    Makino H, Yoshinaga Y, Yamasaki Y, Morita Y, Hashimoto H, Yamamura M (2002) Renal involvement in rheumatoid arthritis: analysis of renal biopsy specimens from 100 patients. Mod Rheumatol 12:148–154CrossRefGoogle Scholar
  23. 23.
    Kuroda T, Tanabe N, Kobayashi D, Sato H, Wada Y, Murakami S et al Association between clinical parameters and amyloid-positive area in gastroduodenal biopsy in reactive amyloidosis associated with rheumatoid arthritis. Rheumatol Int. (in press)Google Scholar
  24. 24.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al (1988) The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324PubMedCrossRefGoogle Scholar
  25. 25.
    Saito T, Nishi S, Karasawa R, In H, Hayashi H, Ueno M et al (1995) An ultrastructural study of glomerular basement membrane in rheumatoid arthritis patients with urinary abnormalities. Clin Nephrol 43:360–367PubMedGoogle Scholar
  26. 26.
    Imai E, Horio M, Nitta K, Yamagata K, Iseki K, Tsukamoto Y et al (2007) Modification of the modification of diet in renal disease (MDRD) study equation for Japan. Am J Kidney Dis 50:927–937PubMedCrossRefGoogle Scholar
  27. 27.
    Suzuki A, Ohosone Y, Obana M, Mita S, Matsuoka Y, Irimajiri S et al (1994) Cause of death in 81 autopsied patients with rheumatoid arthritis. J Rheumatol 21:33–36PubMedGoogle Scholar
  28. 28.
    Joss N, McLaughlin K, Simpson K, Boulton-Jones JM (2000) Presentation, survival and prognostic markers in AA amyloidosis. Q J Med 93:535–542CrossRefGoogle Scholar
  29. 29.
    Tanaka F, Migita K, Honda S, Fukuda T, Mine M, Nakamura T et al (2003) Clinical outcome and survival of secondary (AA) amyloidosis. Clin Exp Rheumatol 21:343–346PubMedGoogle Scholar
  30. 30.
    Okuda Y, Takasugi K, Oyama T, Oyama H, Nanba S, Miyamoto T (1997) Intractable diarrhea associated with secondary amyloidosis in rheumatoid arthritis. Ann Rheum Dis 56:535–541PubMedCrossRefGoogle Scholar
  31. 31.
    Kuroda T, Tanabe N, Harada T, Murakami S, Hasegawa H, Sakatsume M et al (2006) Long-term mortality outcome in patients with reactive amyloidosis associated with rheumatoid arthritis. Clin Rheumatol 25:498–505PubMedCrossRefGoogle Scholar
  32. 32.
    Kuroda T, Tanabe N, Sato H, Ajiro J, Wada Y, Murakami S et al (2006) (2006) Outcome of patients with reactive amyloidosis associated with rheumatoid arthritis in dialysis treatment. Rheumatol Int 26:1147–1153PubMedCrossRefGoogle Scholar
  33. 33.
    Sanai T, Nanishi F, Nagata M, Hirano T, Suematsu E, Esaki Y et al (2007) Role of amyloidosis in determining the prognosis of dialyzed patients with rheumatoid arthritis. Rheumatol Int 27:363–367PubMedCrossRefGoogle Scholar
  34. 34.
    Immonen K, Finne P, Hakala M, Kautiainen H, Pettersson T, Gronhagen-Riska C (2008) No improvement in survival of patients with amyloidosis associated with inflammatory rheumatic diseases: data from the Finnish national registry for kidney diseases. J Rheumatol 35:1334–1338PubMedGoogle Scholar
  35. 35.
    Nishi S, Alchi B, Imai N, Gejyo F (2008) New advances in renal amyloidosis. Clin Exp Nephrol 12:93–101PubMedCrossRefGoogle Scholar
  36. 36.
    Samuels B, Lee JC, Engleman EP, Hopper J (1997) Membranous nephropathy in patients with rheumatoid arthritis: relationship to gold therapy. Medicine 57:319–327Google Scholar
  37. 37.
    Horii Y, Muraguchi A, Iwano M, Matsuda T, Hirayama T, Yamada H et al (1989) Involvement of IL-6 mesangial proliferative glomerulonephritis. J Immunol 143:3949–3955PubMedGoogle Scholar
  38. 38.
    Kishimoto T (1989) The biology of interleukin-6. Blood 74:1–10PubMedGoogle Scholar
  39. 39.
    Salmon MI, Gallo G, Poon TP, Goldblat MV, Tchertkoff V (1974) The kidney in rheumatoid arthritis: a study based on renal biopsies. Nephron 12:297–310CrossRefGoogle Scholar
  40. 40.
    Helin H, Korpela M, Mustonen J, Pasternack A (1986) Mild mesangial glomerulopathy: a frequent finding in rheumatoid arthritis patients with hematuria or proteinuria. Nephron 42:224–230PubMedCrossRefGoogle Scholar
  41. 41.
    Hiki Y, Kobayashi Y, Tateno S, Sada M, Kashiwagi N (1982) Strong association of HLA-DR4 with benign IgA nephropathy. Nephron 32:222–226PubMedCrossRefGoogle Scholar
  42. 42.
    Stastny P (1978) Association of B-cell alloantigen Drw4 with rheumatoid arthritis. N Engl J Med 298:869–871PubMedCrossRefGoogle Scholar
  43. 43.
    Barden J, Mullinax F, Waller M (1967) Immunoglobulin levels in rheumatoid arthritis: comparison with rheumatoid factor titer, clinical stage and disease duration. Arthritis Rheum 10:228–234CrossRefGoogle Scholar
  44. 44.
    Ogura T, Takaoka M, Ogata R, Mino Y, Makino H, Hiramatsu M et al (1985) Clinical study of renal injury by gold therapy in patients with rheumatoid arthritis (in Japanese). Jpn J Clin Immun 8:153–160CrossRefGoogle Scholar
  45. 45.
    Miyoshi A, Takaya Y, Kida K, Makino H, Hiramatsu M, Takahashi K et al (1980) d-penicillamine nephropathy. J Clin Electron Microsc 13:55–62Google Scholar
  46. 46.
    Nagakane T, Ogura T, Nishiya K, Natsumeda M, Haramoto T, Sasaki T et al (1990) Immunopathological study of bucillamine-induced nephropathy in patients with rheumatoid arthritis (in Japanese). Jpn J Clin Immunol 13:346–355CrossRefGoogle Scholar
  47. 47.
    Kuroda T, Wada Y, Kobayashi D, Murakami S, Sakai T, Sato H et al (2009) Effective anti-TNF-α therapy can induce rapid resolution and sustained decrease of gastroduodenal mucosal amyloid deposits in reactive amyloidosis associated with rheumatoid arthritis. J Rheumatol 36:2409–2415PubMedCrossRefGoogle Scholar
  48. 48.
    Ogg CS, Cameron JS, Williams DG, Turner DR (1981) Presentation and course of primary amyloidosis of the kidney. Clin Nephrol 15:9–13PubMedGoogle Scholar
  49. 49.
    Nakamura T (2008) Clinical strategies for amyloid A amyloidosis secondary to rheumatoid arthritis. Mod Rheumtol 18:109–118CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Takeshi Kuroda
    • 1
  • Naohito Tanabe
    • 2
  • Daisuke Kobayashi
    • 1
  • Yoko Wada
    • 1
  • Shuichi Murakami
    • 1
  • Masaaki Nakano
    • 3
  • Ichiei Narita
    • 1
  1. 1.Division of Clinical Nephrology and RheumatologyNiigata University Graduate School of Medical and Dental SciencesNiigata CityJapan
  2. 2.Department of Health and Nutrition, Faculty of Human Life StudiesUniversity of Niigata PrefectureNiigataJapan
  3. 3.Department of Medical Technology, School of Health Sciences, Faculty of MedicineNiigata UniversityNiigata CityJapan

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