Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response

doi:10.1016/j.humpath.2007.04.013

Human Pathology

Volume 38, Issue 12, December 2007, Pages 1798-1809

https://doi.org/10.1016/j.humpath.2007.04.013 Get rights and content

Summary

We retrospectively reviewed the clinicopathological features of a series of 68 renal AA amyloidosis observations collected between 1990 and 2005. The amyloidogenic disease was a chronic infection (40.8%), a chronic inflammation (38%), a tumor (9.9%), a hereditary disease (9.9%), or was undetermined in 1.4% of cases. Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively. The distribution pattern of glomerular amyloid deposits was mesangial segmental (14.7%), mesangial nodular (26.5%), mesangiocapillary (32.3%), and hilar (26.5%). Glomerular form was observed in 80.9% of cases and vascular form in 19.1%. AA amyloidosis-related inflammation was noted in 30 patients (44.1%) and appeared as a multinucleated giant cell reaction (27.9%) or a glomerular inflammatory infiltrate (25%), including glomerular crescents (17.6%). At the end of follow-up, 26 patients (38.2%) showed end-stage renal disease. The clinical presentation of glomerular and vascular forms was distinct with a clear predominance of proteinuria in glomerular form. Inflammatory reaction was preferentially observed in biopsies with a codeposition of immunoglobulin chains and/or complement factors in AA amyloid deposits. The distribution pattern of glomerular amyloid deposits and glomerular inflammatory reaction were independent factors influencing proteinuria level. Tubular atrophy, abundance, and distribution pattern of glomerular amyloid deposits at the time of biopsy were independent predictors of renal outcome. In conclusion, the glomerular involvement appeared as the determining histological factor for clinical manifestations and outcome of renal AA amyloidosis. AA amyloidosis-related inflammation could partly result from an immune response directed against AA fibrils and could induce amyloid resolution and crescents.

Introduction

Amyloidoses constitute a heterogeneous group of diseases characterized by extracellular deposition of amyloid proteins in different tissues and organs. Amyloid deposits are identified on the basis of their morphologic, structural, and tinctorial characteristics [1]. In human pathology, 25 different proteins are known to have the ability to aggregate in insoluble fibrillar deposits, including amyloid A protein responsible for AA amyloidosis [1]. The AA amyloid proteins result from a proteolytic cleavage of acute phase serum amyloid A protein (A-SAAs) usually in the C-terminal half of the 104 amino acid residues long precursor. Acquired and hereditary diseases can lead to systemic AA amyloidosis provided they are associated with chronic inflammation. Renal involvement, extremely frequent in systemic AA amyloidosis, is a major cause of morbidity and mortality. The aim of this study was to analyze the histological characteristics of a series of renal AA amyloidosis and their possible clinical implications. We were interested in the distribution pattern of amyloid deposits in renal parenchyma and more particularly in the 2 principal histological forms of renal AA amyloidosis, that is, glomerular and vascular forms [2], [3], [4], [5]. We also studied the inflammatory reaction related to renal AA amyloidosis. Although inflammation against amyloid deposits plays an important role in Aβ and Aβ2m amyloidoses [6], [7], few data are currently available on this subject in renal AA amyloidosis.

Section snippets

Patients and materials

One hundred seventy-four cases of renal amyloidosis were observed between January 1990 and December 2005 in 3 departments of renal Pathology (Hôpital Necker, Hôpital Pitié-Salpêtrière, and Hôpital Saint-Louis). They included 68 cases (39.1%) of AA amyloidosis and 105 cases (60.3%) of AL amyloidosis (AA/AL amyloidosis ratio, 1:1.5). The remaining case concerned a patient with a mutation in the fibrinogen A alpha chain gene. We gathered in our series the 68 cases of renal AA amyloidosis and

Clinical findings

Among the 68 observations of renal AA amyloidosis, 2 were previously reported [11], [12]. These 68 patients included 33 females and 35 males. The mean age at diagnosis was 57.6 ± 15.1 years, 58.9 ± 16.5 years for women and 56.4 ± 13.8 years for men. A total of 40 (58.8%) patients originated from Europe, 19 (27.9%) from North Africa, 6 (8.8%) from sub-Saharan Africa, 2 (3%) from Turkey, and 1 (1.5%) from Armenia. All the amyloidogenic diseases are listed in Table 1, except for 3 patients without

AA/AL amyloidosis ratio and etiology of AA amyloidosis

The relative proportion of AA amyloidosis in systemic amyloidosis largely varies according to geographic area. AA/AL amyloidosis ratio was 2 per 1 in west Europe versus 1 per 17 in the United States of America [13]. In our study, this ratio was 1 per 1.5. However, it was 1 per 0.8 during the previous decade with an unchanged recruitment (personal data). This result tends to confirm the current preponderance of renal AL amyloidosis in France.

Etiology of AA amyloidosis in western countries has

Acknowledgments

The authors would like to thank Prs J. P. Grünfeld, G. Deray, C. Legendre, J. C. Piette, S. Herson, P. Bourgeois, L. -J. Couderc, and Drs P. Lebon, L. Dupouët, C. Barbanel, J. Montseny, J. -M. Trawale, G. Moret, and F. Beaufils for their kind contributions to this study.

References (32)

L.C. Racusen et al.
The Banff 97 working classification of renal allograft pathology
Kidney Int
(1999)
B.P. Hazenberg et al.
Clinical and therapeutic aspects of AA amyloidosis
Baillieres Clin Rheumatol
(1994)
R. Hrncic et al.
Antibody-mediated resolution of light chain-associated amyloid deposits
Am J Pathol
(2000)
G.J. Thomas et al.
The potential role of human kidney cortex cysteine proteinases in glomerular basement membrane degradation
Biochim Biophys Acta
(1989)
C. Röcken et al.
Amyloid in surgical pathology
Virchows Arch
(2003)
P. Westermark et al.
Morphologic and chemical variation of the kidney lesions in amyloidosis secondary to rheumatoid arthritis
Lab Invest
(1979)
H.M. Falck et al.
Predominantly vascular amyloid deposition in the kidney in patients with minimal or no proteinuria
Clin Nephrol
(1983)
L.M. Looi
Histomorphological variations in systemic AA amyloidosis: clues of AA protein polymorphism
Histopathology
(1989)
H. Uda et al.
Two distinct clinical courses of renal involvement in rheumatoid patients with AA amyloidosis
J Rheumatol
(2006)
N.J. Scolding et al.
Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy
Brain
(2005)

A. Argiles et al.

Phagocytosis of dialysis-related amyloid deposits by macrophages

Nephrol Dial Transplant

(2002)

T. Watanabe et al.

Morphological and clinical features of renal amyloidosis

Virchows Arch A Pathol Anat Histol

(1975)

H. Shiiki et al.

Renal amyloidosis. Correlations between morphology, chemical types of amyloid protein and clinical features

Virchows Arch A Pathol Anat Histopathol

(1988)

L. Larvol et al.

Reversible nephrotic syndrome in Crohn's disease complicated with renal amyloidosis

Gastroenterol Clin Biol

(1998)

A. Sbai et al.

Amyloid goiter as the initial manifestation of systemic amyloidosis due to familial Mediterranean fever with homozygous MEFV mutation

Thyroid

(2001)

M.A. Gertz et al.

Secondary systemic amyloidosis: response and survival in 64 patients

Medicine (Baltimore)

(1991)

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Original contributionClinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response

Summary

Introduction

Section snippets

Patients and materials

Clinical findings

AA/AL amyloidosis ratio and etiology of AA amyloidosis

Acknowledgments

Kidney Int

Baillieres Clin Rheumatol

Am J Pathol

Biochim Biophys Acta

Amyloid in surgical pathology

Virchows Arch

Morphologic and chemical variation of the kidney lesions in amyloidosis secondary to rheumatoid arthritis

Lab Invest

Predominantly vascular amyloid deposition in the kidney in patients with minimal or no proteinuria

Clin Nephrol

Histomorphological variations in systemic AA amyloidosis: clues of AA protein polymorphism

Histopathology

Two distinct clinical courses of renal involvement in rheumatoid patients with AA amyloidosis

J Rheumatol

Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy

Brain