Romera Ana (1), Ortega Rosa (2,3) , Espinosa Mario (1), Gómez Jose (1), Agüera Maria Luisa (1), López-Rubio Fernando (2), Aljama Pedro (1)

(1) Department of Nephrology, University Hospital Reina Sofia, Córdoba - Spain, (2) Department of Anatomy Pathology, University Hospital Reina Sofia, Córdoba –Spain, (3) Member of GLOSEN (Group for the Study of Glomerular Diseases of the Spanish Society)

case presentation

The patient is A 77-year-old man with multiple medical problems including type 2 diabetes mellitus on treatment with oral antidiabetic, COPD, hypercholesterolemia, arthrosis and benign prostatic hyperplasia. His arthrosis was long-standing and had been medically managed in the past with non-steroidal anti-inflammatory drugs.

The patient presented to our institution with fatigue, anorexia and weight loss that worsened over the previous weeks. Three months before admission, his serum creatinine was 1.1 mg/dl. Urine analysis at this time showed microhematuria and proteinuria was 30 mg/dl.

On physical examination the patient was noted to have pale conjunctivae, and flexion of the distal interphalangeal joints with deviation of the fingers.

Laboratory test disclosed: Hemoglobin 9.1 gr/dl (normal three months before), creatinine 3.8 mg/dl, blood urea nitrogen 72mg/dl, K 5 Meq/l, Ca 8.8 mg/dl, Protein 7gr/dl, albumin 2.10 gr/dl, ESR 121mm/hour. Negative anti-neutrophil cytoplasmic and nuclear antibodies. Anti-IgA antibodies were elevated at 832 mg/dl (normal 90-450 mg/dl), C4 was decreased at 9.38 mg/dl (normal 15-50 mg/dl), and anti-GBM antibodies were positive (199 mg/dl; normal <10 mg/dl). Serum rheumatoid factor was negative. Urinalysis: proteinuria over 7gr/24h and microhematuria.

The renal ultrasound showed borderline large kidneys.

RENAL BIOPSY FINDINGS

Renal biopsy tissue contained 12 glomerulus, two of which were sclerosed (16%). Six of the 11 (54%) non-sclerotic glomerulus had cellular crescents (Fig 1). Amyloid deposition, confirmed by congo red staining (Fig 2), polarization and immunoperoxidase staining with anti-amyloid A antibody, was found in glomerulus and vessels. In glomerulus, amyloid deposits extended from mesangium to GBM (Fig 3) and some times until extracapillary space (Fig 2).
Immunofluorescence studies revealed lineal deposit of IgG along the glomerular basal membrane. Kappa and lambda light chain were negatives.
On electron microscopic examination showed mesangial and GBM deposits with straight, non-branching fibrils disorderly organized characteristic of amyloidosis (Fig 4, 5).Electrodense deposits were not observed. The crescents seen in glomerulus were composed of proliferating parietal epithelial cells.

FINAL DIAGNOSIS

AA (Secondary) Renal Amyloidosis associated with anti-GBM antibody crescentic Glomerulonephritis (Type I).

Polyarthritis without meeting criteria of rheumatoid arthritis.

 

Follow up

Given the finding of renal amyloidosis, a bone marrow biopsy was done which showed a hypocellular marrow with no evidence of amyloidosis or plasma cell dyscrasia. Monoclonal bands were not seen on either serum or urine inmunofixation electrophoreses.

Methylprednisolone was given intravenously (500 mg/24h x three boluses) followed by oral prednisone (1mg/kg/day);  oral cyclophosphamide was withdrawn because of severe leucopenia. Because of rapid deterioration of renal function he started hemodialysis and treatment with 12 sessions of plasmapheresis.  Despite aggressive therapy our patient remained dependent on hemodialysis during five months, and eventually died.

 

DISCUSSION

Crescentic glomerulonephritis is a non-specific morphologic manifestation of severe glomerular injury frequently associated with the clinical syndrome of rapidly progressive glomerulonephritis. Without treatment, crescentic glomerulonephritis leads to terminal renal failure in less than six months in 80-90% of cases (1). Renal amyloidosis is a disorder of protein folding in which normal soluble proteins undergo conformational change and are deposited in the extracellular space in an fibrillar form. Accumulation of these fibrils causes progressive disruption of the structure and function of kidney. Chronic Renal dysfunction is one of the most common presenting features of patients with systemic amyloidosis.

Crescentic glomerulonephritis associated with renal amyloidosis has rarely been reported. We are aware of only about eighteen cases, most of these patients also had rheumatoid arthritis (2-4), and in some patients were associated with positive anti-neutrophil cytoplasmic and anti-nuclear antibodies. In only one case amyloidosis has been associated with anti-glomerular basement membrane (anti-GBM) crescentic glomerulonephritis.(5).

We add to this growing body of literature a new case of renal amyloidosis associated with anti-GBM crescentic glomerulonephritis.
In patients with rheumatoid arthritis, amyloidosis and crescentic glomerulonephritis it is suggested that a non-immune mechanism may play a role in the crescentic glomerulonephritis. It is proposed that destruction of the glomerular basement membrane at sites of amyloid deposition, and the resultant breaks would conceivably allow fibrin into Bowman´s space to act as a scaffold for proliferating parietal epithelial cells (2, 8).

More rare is the relation of crescentic glomerulonephritis with anti-GBM antibodies and renal amyloidosis in which an immune mechanism must play an important role. In our patient amyloid deposition was observed in GBM.This amyloid deposition could induce GBM disruption, and alteration of quaternary structure of the NC1 domain of type IV collagen, thereby facilitating epitope exposure, immune system activation, and autoantibody binding as has been reported in experimental models (11).
Nevertheless, the findings of our case certainly suggest that it should be considered the development of type I crescentic glomerulonephritis and renal amyloidosis in  patients with acute renal failure.

 

REFERENCES

1. Jennette JC. Rapidly progressive crescentic glomerulo-nephritis. Kidney Int 2003; 63: 1164-1177.
2. Murakami H, Ura N, Nagao K et al. Rheumatoid arthritis associated with renal amyloidosis and crescentic glomerulo-nephritis. Intern Med 1998; 37: 94-97.
3. Boers M, Croonen AM, Dijkmans BA et al. Renal findings in rheumatoid arthritis: clinical aspects of 132 necropsies. Ann Rheum Dis 1987; 46: 658-663.
4. Icardi A, Araghi P, Ciabattoni M, Romano U, Lazzarini P, Bianchi G. Kidney involvement in rheumatoid arthritis. Reumatismo 2003; 55: 76-85.
5. Diaz Gallo C, Mauri JM, Poveda R et al. Renal amyloidosis associated with antiglomerular basement membrane disease. Nephron 1990; 56: 335-336.
6. Andreu FJ, Almirall J, Jurado I, Larrosa M, Carreras M, Rey M. Renal failure in a patient with two renal diseases: renal amyloidosis and rapidly progressive glomerulonephritis. Nephrol Dial Transplant 1997; 12: 341-343.
7. Galicia Basart MA, Codina S, Cantarell C, Carrera M, Piera L. Renal amyloidosis and extracapillary glomerulonephritis. A rare association. Med Clin (Barc) 1998; 90: 23-24.
8. Kiyama S, Sakemi T, Shimokama T, Baba N, Watanabe T. Crescentic glomerulonephritis associated with renal amyloidosis. Jpn J Med 1991; 30: 238-242.
9. Moroni G, Banfi G, Maccario M, Mereghetti M, Ponticelli C. Extracapillary glomerulonephritis and renal amyloidosis. Am J Kidney Dis 1996; 28: 695-699.
10. Bernheim J, Bernheim J. The patient with two renal diseases: crescentic glomerulonephritis and renal AA amyloid. Nephrol Dial Transplant 1999; 14: 1315-1316.
11. Revert F, Merino R, Monteagudo C, Macias J, Peydró A, Alcocer J, Muniesa P, Marquina R, Blanco M, Iglesias M, Revert-Ros F, Merino J, Saus J. Increased Goodpasture Antigen-Binding Protein Expression Induces Type IV Collagen Disorganization and Deposit of Immunoglobulin A in Glomerular Basement Membrane. Am J Pathol 2007; 171: 1419–1430.

 

ACKNOWLEDEMENTS

This work was supported in part by the Fundación Nefrológica.
Conflict of interest statement. None declared.

 

CORRESPONDENCE

Rosa Ortega, MD
Department of anatomy Pathology, University Hospital Reina Sofia
Avda Méndez Pidal s/n
14004 Córdoba
Spain.
Phone +34957010409