- Email: [email protected]
Secondary Renal Amyloidosis due to Long-Standing Tubulointerstitial Nephritis in a Patient With Sjögren Syndrome
CASE REPORT
Secondary Renal Amyloidosis due to Long-Standing Tubulointerstitial Nephritis in a Patient With Sjögren Syndrome Vanessa Ooms, MD, Marc Decupere, MD, Evelyne Lerut, MD, Yves Vanrenterghem, MD, PhD, and Dirk R.J. Kuypers, MD, PhD ● A 53-year-old patient with long-standing primary Sjögren syndrome presented with acute renal failure and nephrotic syndrome caused by secondary (AA) renal amyloidosis. Ten years before, he had been admitted because of exacerbation of the systemic disease. At that time, a pseudolymphoma of the kidney was diagnosed. To our knowledge, this is the first report of a patient with primary Sjögren syndrome and secondary (AA) amyloidosis with amyloid deposition in the kidneys causing nephrotic syndrome. Am J Kidney Dis 46:E75-E80. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Sjögren syndrome; tubulointerstitial nephritis; secondary amyloidosis; AA amyloidosis.
P
RIMARY SJÖGREN SYNDROME is an autoimmune disorder characterized by polyclonal B-cell activation, as well as lymphocytic infiltration of exocrine glands, especially the lacrimal and salivary glands. This lymphocytic infiltration also can affect the kidneys, resulting in interstitial nephritis. In our patient, longstanding chronic interstitial nephritis was complicated by secondary (AA) amyloidosis, causing renal failure and nephrotic syndrome. CASE REPORT
A 53-year-old man was admitted in November 2003 because of progressive dyspnea on exertion, fatigue, and generalized edema. Primary Sjögren syndrome had been diagnosed in 1985. This diagnosis was based on the presence of 4 of 6 of the current American-European revised rules for classification of Sjögren syndrome1: ocular and oral symptoms (sicca syndrome), ocular signs (positive Schirmer test result), and positive glandular histological characteristics with polyclonal lymphocytic infiltration in a tissue biopsy specimen of a salivary gland. None of the exclusion criteria precluding the diagnosis of primary Sjögren syndrome1 were present in the patient. Test results for antinuclear factor and antiextractable nuclear antigen antibodies were negative. Erythrocyte sedimentation rate (ESR) was elevated (40 mm/h; normal range, 1 to 10 mm/h), and test results for rheumatoid factor repeatedly were negative. Between 1985 and 1989, the patient had at least 5 documented relapses of nodular scleritis, with fever, weight loss, and an elevated ESR (ⱖ100 mm/h). On all occasions, the patient was treated in the acute phase with methylprednisolone, although after discharge from the hospital, the patient’s compliance with maintenance corticosteroid therapy was doubtful. A cardiac pacemaker was implanted in 1989 because of complete atrioventricular heart block. One year later, in 1990, the patient underwent cardiac surgery with aortic valve replacement because of severe aortic regurgitation. During open-heart surgery, edematous infiltration of the valvular ring and cusps was noticed, as well as swelling of the interventricular myocardial muscle wall. At that time, no further investigation was initiated, but histological exami-
nation of the native aortic valve showed subendocardial fibrosis and negative Congo red staining. In 1993, the patient was hospitalized because of exacerbation of his systemic disease, with anorexia, weight loss, and fever. ESR was elevated (140 mm/h), and C-reactive protein level was 185 mg/L (normal range, ⱕ5 mg/L). There was polyclonal hypergammaglobulinemia (gamma globulin, 1.93 g/100 mL; normal range, 0.78 to 1.52 g/100 mL), whereas antinuclear factor and antiextractable nuclear antigen antibodies remained negative; in particular, anti-Ro/SSA and anti-La/ SSB antibodies were negative. Results of serum creatinine and urine analysis at that time were completely normal; there were no signs of type 1 renal tubular acidosis, hypokalemia, or diabetes insipidus. Abdominal computed tomography showed multiple bilateral hypodense lesions (13 to 17 Hounsfield units) in both kidneys and enlarged retroperitoneal lymphoid glands, suggestive of a lymphoproliferative disease or bilateral renal cell carcinoma (Fig 1). Subsequently, a CT-guided renal biopsy of a hypodense lesion in the right kidney was performed. Light microscopy of renal tissue showed diffuse interstitial infiltration by lymphocytes, histiocytes, and plasma cells, locally organized into a follicular pattern (Fig 2). Glomeruli had a normal appearance. Immunohistochemical staining confirmed the presence of immunoglobulin M– and immunoglobulin G–positive plasma cells with mild predominance of light chain–positive plasma cells. However, no evidence was found for malignancy or monotypic B-cell clone. The
From the Departments of Nephrology and Renal Transplantation and Pathology, University Hospitals Leuven, Belgium. Received March 14, 2005; accepted in revised form July 11, 2005. Originally published online as doi:10.1053/j.ajkd.2005.07.019 on September 14, 2005. Address reprint requests to Dirk R.J. Kuypers, MD, PhD, Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4605-0035$30.00/0 doi:10.1053/j.ajkd.2005.07.019
American Journal of Kidney Diseases, Vol 46, No 5 (November), 2005: E75-E80
e75
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OOMS ET AL
Fig 1. Abdominal computed tomographic scan shows bilateral multifocal renal parenchymal hypodense lesions and multiple retroperitoneal adenopathies.
diagnosis of pseudolymphoma was made, as can be encountered in some patients with bacterial pyelonephritis or other infectious disease and such systemic diseases as Sjögren syndrome. Further investigations did not show an infectious agent; therefore, treatment with methylprednisolone was started, resulting in prompt regression of inflammatory signs after a few days. After 1 month of treatment, the patient’s C-reactive protein level decreased to 48 mg/L, and ESR was 56 mm/h. After 2 months, a new abdominal computed tomographic scan was performed. This scan showed that hypodense lesions in both kidneys were stable in size, and retroperitoneal enlarged glands had disappeared. Three months later, the patient was lost to follow-up. On admission in November 2003, physical examination showed an apical grade-3 systolic heart murmur. There was very severe pitting edema of both legs, and central venous pressure was normal. The left eye protruded, with blue discoloration of the sclera. Laboratory tests showed normocytic anemia with a hemoglobin concentration of 11.7 g/dL (117 g/L) and normal reticulocyte count, white blood cell count of 11 ⫻ 103/L (11 ⫻ 109/L), platelet count of 350 ⫻ 103/L (350 ⫻ 109/L), and ESR of 113 mm/h. Serum creatinine concentration was 4.95 mg/dL (437 mol/L), blood urea nitrogen level was 126 mg/dL (45 mmol/L), and serum albumin concentration
was 2.2 g/dL (22 g/L). Liver enzyme levels were normal. There was hypercholesterolemia, with a total cholesterol level of 270 mg/dL (6.98 mmol/L) and low-density lipoprotein cholesterol level of 177 mg/dL (4.57 mmo/L). Urine sediment showed proteinuria and hematuria (277 red blood cells/L). Twenty-four–hour urine collection contained 13 g of protein, whereas calculated creatinine clearance was 11 mL/min (0.18 mL/s). Serum immunoglobulin and complement levels were normal. Serum electrophoresis showed an acute reactive process (albumin fraction, 37% [normal range, 56.8% to 68%]; ␣1-globulin fraction, 11.7% [normal range, 4.8% to 7.4%]; ␣2-globulin fraction, 19.5% [normal range, 7.3% to 12.3%]; -globulin fraction, 14.1% [normal range, 7.3% to 11.1%]), and serum immunofixation showed no evidence for a monoclonal fraction. Urine immunofixation did not detect paraprotein. Antinuclear factor was negative, and antineutrophil cytoplasmic autoantibody titer was 1/160, with normal antiproteinase 3 and antimyeloperoxidase concentrations. There was immunity for hepatitis B. Hepatitis C serological test result was negative. Because of persistent dyspnea, echocardiography was performed. The latter showed a hypocontractile left ventricle with diffuse hypokinesia (ejection fraction, 57%) and diastolic dysfunction, a moderate aortic (Björk-Shiley) prosthetic valve and mitral valve regurgitation, and pulmonary
SECONDARY RENAL AMYLOIDOSIS IN SJÖGREN SYNDROME
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Fig 2. First renal biopsy specimen shows diffuse interstitial infiltration by lymphocytes, histiocytes, and plasma cells locally organized into a follicular pattern. (Silver methenamine stain; original magnification 3 ⴛ20.)
hypertension (41 mm Hg). Abdominal ultrasound showed normal bipolar diameter of both kidneys (left, 11.7 cm; right, 11 cm); a 2.7-cm diameter mass was located in the right kidney. Compared with the computed tomographic scan of the abdomen in 1993, this lesion was stable in size. Because of the new-onset nephrotic syndrome of unknown cause in combination with acute renal failure, another renal biopsy was performed. Histological examination was very similar to that of 1993, with a dense mixed inflammatory interstitial infiltrate containing plasma cells, lymphocytes, and histiocytes (Fig 3). Again, immunohistochemistry showed no evidence of monoclonal cell expansion. Glomeruli were enlarged and showed fibrosis of the capsule. The mesangium of glomeruli was broadened because of eosinophilic hyaline deposits. Congo red staining of these hyaline deposits was positive; subsequently, the presence of AA amyloid was confirmed by means of the standard immunohistochemical technique using monoclonal AA antiserum (DakoCytomation, Glostrup, Denmark) at a dilution of 1/100. The diagnosis of a secondary AA-type amyloidosis caused by chronic inflammation of Sjögren syndrome was concluded. Treatment with oral methylprednisolone was started promptly at 1 mg/kg of body weight per day. After 4 weeks
of therapy, improvement in renal function was noticed, whereas proteinuria decreased significantly (serum creatinine level, from 5.0 to 3.7 mg/dL [442 to 327 mol/L]; creatinine clearance according to Cockcroft-Gault, from 11 to 20 mL/min [0.18 to 0.33 mL/s]; and proteinuria, from 13 to 6 g/24 h). Corticosteroid dosage was tapered very slowly, and 10 months later, a maintenance dose of 6 mg of prednisolone was adhered to. Partial remission of nephrotic syndrome was achieved with a decrease in proteinuria to protein of 3 g/d. Serum creatinine level improved to 2.6 mg/dL (230 mol/L), corresponding to a calculated creatinine clearance of 24 mL/min (0.4 mL/s). The reporting of this case was approved by the Institutional Review Board of the Faculty of Medicine, University of Leuven (ML No 3118).
DISCUSSION
We present a patient with Sjögren syndrome in whom pseudolymphoma of the kidneys was diagnosed in 1993. Ten years later, in 2003, he presented with nephrotic syndrome and renal insufficiency caused by secondary (AA) renal
e78
OOMS ET AL
Fig 3. Second biopsy specimen shows dense mixed inflammatory interstitial infiltrate containing plasma cells, lymphocytes, and histiocytes with hyaline deposits in glomeruli and vessel walls. Congo red staining of these hyaline deposits was positive. (Silver methenamine stain; original magnification 3 ⴛ10.)
amyloidosis superimposed on chronic tubulointerstitial nephritis. Sjögren syndrome is a chronic inflammatory disorder characterized by polyclonal B-cell activation, as well as lymphocytic infiltration of exocrine glands, especially the lacrimal and salivary glands. Because of this B-cell activation, malignant lymphoproliferative disorders occur with a greater frequency in patients with Sjögren syndrome.2 When B cells are pleomorphic, but fail to meet criteria for true malignancy, the term pseudolymphoma often is applied. This may present as lymphadenopathy or functional impairment of the affected organ, such as kidney or lung. Lymphocytic infiltration in patients with Sjögren syndrome can affect the kidneys, resulting in interstitial nephritis. Glomerular involvement is much less common in patients with Sjögren syndrome, and the exact pathogenesis is unclear. The prevalence of renal involvement in patients with Sjögren syndrome is not well known, but overall, occurs infrequently.3-5
Primary Sjögren syndrome was diagnosed in this patient in 1985 in accordance with the current American-European revised rules for classification of Sjögren syndrome.1 Between 1985 and 1989, he experienced several documented relapses of scleritis, with fever and chronic inflammation assessed by means of laboratory biochemistry. The patient had severe biopsy-proven chronic interstitial nephritis since 1993 that was not treated long enough because of patient noncompliance and skipping of scheduled follow-up visits. Consequently, the long-standing chronic inflammation triggered the development of secondary (AA) amyloidosis with renal and suspected cardiac involvement. AA amyloidosis is characterized by extracellular tissue deposition of serum amyloid A fibrils that,6 if left untreated, leads to serious disease with significant mortality caused by end-stage renal disease, infection, heart failure, or bowel perforation.7 The risk for developing systemic AA amyloidosis is related to the continuous and subclinical
SECONDARY RENAL AMYLOIDOSIS IN SJÖGREN SYNDROME
inflammation that occurs during attack-free periods and, consequently, the magnitude and persistency of elevated serum amyloid A levels. The clinical course of this patient with recurrent episodes of documented disease activity, a history of noncompliance with corticosteroid maintenance therapy, and the final presentation in 2003 with nephrotic syndrome are suggestive of a causal relationship between persistent Sjögren syndrome–associated inflammation and the development of renal AA amyloidosis. Unfortunately, serum amyloid A levels were not determined. Unique in this setting is the concurrent finding of persistent chronic tubulointerstitial nephritis and AA amyloid depositions in the repeated biopsy specimen. Because of the latter finding and the clinical history, we assume that the chronic interstitial nephritis itself, next to extrarenal persistent disease activity, was the stimulus for the development of renal AA amyloidosis. Because the preferred therapy for AA amyloidosis still is treatment of the underlying inflammatory disease,8 our patient was treated with corticosteroids and achieved partial remission of nephrotic syndrome and improvement in renal function, probably predominantly through resolving the interstitial inflammatory component. We suggest that therapeutic control of the concurrent tubulointerstitial parenchymatous inflammation might have had a partially beneficial role in the clinical course of Sjögren syndrome–related renal AA amyloidosis. This unusual presentation indicates that a repeated renal biopsy seems warranted in patients with long-standing Sjögren disease who develop renal insufficiency or (nephrotic-range) proteinuria. The occurrence of amyloidosis in patients with primary Sjögren syndrome remains rare. In previous cases, amyloidosis was localized in the dermis,9,10 lung,11-14 tongue,15 or breasts.16 Only 1 report showed the concomitant diagnosis of primary Sjögren syndrome and systemic AL amyloidosis.17 The occurrence of amyloidomas (amyloidosis presenting as a tumor) in patients with Sjögren syndrome is better documented. Sites of amyloidomas in these patients included lung, tongue, neck, bladder, esophagus, and lower limbs.18 To our knowledge, this is the first report of a patient with long-standing primary Sjögren syn-
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drome and secondary renal (AA) amyloidosis resulting in a nephrotic syndrome. Primary Sjögren syndrome therefore should be regarded as a novel predisposing condition for renal AA amyloidosis. REFERENCES 1. Vitali C, Bombardieri S, Jonsson R, et al: Classification criteria for Sjögren’s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554-558, 2002 2. Mariette X: Lymphomas in patients with Sjögren’s syndrome: Review of the literature and physiopathologic hypothesis. Leuk Lymphoma 33:93-99, 1999 3. Goules A, Masouridi S, Tzioufas AG, Ioannidis JP, Skopouli FN, Moutsopoulos HM: Clinically significant and biopsy-documented renal involvement in primary Sjögren syndrome. Medicine (Baltimore) 79:241-249, 2000 4. Bossini N, Savoldi S, Franceschini F, et al: Clinical and morphological features of kidney involvement in primary Sjögren’s syndrome. Nephrol Dial Transplant 16:23282336, 2001 5. Kwon YJ, Park JH, Kim SW, et al: Sjögren’s syndrome with acute renal failure. J Korean Med Sci 13:665-669, 1998 6. Glenner GG: Amyloid deposits and amyloidosis. The beta-fibrilloses. N Engl J Med 302:1333-1343, 1980 7. Tanaka F, Migita K, Honda S, et al: Clinical outcome and survival of secondary (AA) amyloidosis. Clin Exp Rheumatol 21:343-346, 2003 8. Gillmore JD, Lovat LB, Persey MR, et al: Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 358:24-29, 2001 9. Pablos JL, Cogolludo V, Pinedo F, Carreire PE: Subcutaneous nodular amyloidosis in Sjögren’s syndrome. Scand J Rheumatol 22:250-251, 1993 10. Inazumi T, Hakuno M, Yamada H, et al: Characterisation of the amyloid fibril from primary localized cutaneous nodular amyloidosis associated with Sjögren’s syndrome. Dermatology 189:125-128, 1994 11. Kobayashi H, Matsuoka R, Kitamura S, Tsunoda N, Saito K: Sjögren’s syndrome with multiple bullae and pulmonary nodular amyloidosis. Chest 94:438-440, 1988 12. Milburn JM, Kay D, Ridpat C: Pulmonary nodular amyloidosis in a patient with Sjögren’s syndrome diagnosed by transthoracic biopsy. J La State Med Soc 146:395-398, 1994 13. Wong BC, Wong KL, Ip MS, Wang EP, Chan KW, Cheng LC: Sjögren’s syndrome with amyloid A presenting as multiple pulmonary nodules. J Rheumatol 21:165-167, 1994 14. Srinivas P, Liam CK, Jayaram G: Localised nodular pulmonary amyloidosis in a patient with sicca syndrome. Med J Malaysia 55:385-387, 2000 15. Haraguchi H, Ohashi K, Yamada M, Hasegawa M, Maeda S, Komatsuzaki A: Primary localized nodular tongue amyloidosis associated with Sjögren’s syndrome. ORL J Otorhinolaryngol Relat Spec 1:60-63, 1997 16. Kambouchner M, Godmer P, Guillevin L, Raphael M, Droz D, Martin A: Low grade marginal zone B cell lym-
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phoma of the breast associated with localised amyloidosis and corpora amylacea in a woman with long standing primary Sjögren’s syndrome. J Clin Pathol 56:74-77, 2003 17. Delevaux I, Andre M, Amoura Z, Kémény J-L, Piette J-C, Aumaître O: Concomitant diagnosis of primary Sjögren’s
OOMS ET AL
syndrome and systemic AL amyloidosis. Ann Rheum Dis 60:694-695, 2001 18. Ideura H, Tsukada Y, Maezawa A, Ueki K, Nojima Y, Naruse T: Sjögren’s syndrome and multiple amyloidomas. J Rheumatol 27:1325-1326, 2000
Secondary Renal Amyloidosis due to Long-Standing Tubulointerstitial Nephritis in a Patient With Sjögren Syndrome Vanessa Ooms, MD, Marc Decupere, MD, Evelyne Lerut, MD, Yves Vanrenterghem, MD, PhD, and Dirk R.J. Kuypers, MD, PhD ● A 53-year-old patient with long-standing primary Sjögren syndrome presented with acute renal failure and nephrotic syndrome caused by secondary (AA) renal amyloidosis. Ten years before, he had been admitted because of exacerbation of the systemic disease. At that time, a pseudolymphoma of the kidney was diagnosed. To our knowledge, this is the first report of a patient with primary Sjögren syndrome and secondary (AA) amyloidosis with amyloid deposition in the kidneys causing nephrotic syndrome. Am J Kidney Dis 46:E75-E80. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Sjögren syndrome; tubulointerstitial nephritis; secondary amyloidosis; AA amyloidosis.
P
RIMARY SJÖGREN SYNDROME is an autoimmune disorder characterized by polyclonal B-cell activation, as well as lymphocytic infiltration of exocrine glands, especially the lacrimal and salivary glands. This lymphocytic infiltration also can affect the kidneys, resulting in interstitial nephritis. In our patient, longstanding chronic interstitial nephritis was complicated by secondary (AA) amyloidosis, causing renal failure and nephrotic syndrome. CASE REPORT
A 53-year-old man was admitted in November 2003 because of progressive dyspnea on exertion, fatigue, and generalized edema. Primary Sjögren syndrome had been diagnosed in 1985. This diagnosis was based on the presence of 4 of 6 of the current American-European revised rules for classification of Sjögren syndrome1: ocular and oral symptoms (sicca syndrome), ocular signs (positive Schirmer test result), and positive glandular histological characteristics with polyclonal lymphocytic infiltration in a tissue biopsy specimen of a salivary gland. None of the exclusion criteria precluding the diagnosis of primary Sjögren syndrome1 were present in the patient. Test results for antinuclear factor and antiextractable nuclear antigen antibodies were negative. Erythrocyte sedimentation rate (ESR) was elevated (40 mm/h; normal range, 1 to 10 mm/h), and test results for rheumatoid factor repeatedly were negative. Between 1985 and 1989, the patient had at least 5 documented relapses of nodular scleritis, with fever, weight loss, and an elevated ESR (ⱖ100 mm/h). On all occasions, the patient was treated in the acute phase with methylprednisolone, although after discharge from the hospital, the patient’s compliance with maintenance corticosteroid therapy was doubtful. A cardiac pacemaker was implanted in 1989 because of complete atrioventricular heart block. One year later, in 1990, the patient underwent cardiac surgery with aortic valve replacement because of severe aortic regurgitation. During open-heart surgery, edematous infiltration of the valvular ring and cusps was noticed, as well as swelling of the interventricular myocardial muscle wall. At that time, no further investigation was initiated, but histological exami-
nation of the native aortic valve showed subendocardial fibrosis and negative Congo red staining. In 1993, the patient was hospitalized because of exacerbation of his systemic disease, with anorexia, weight loss, and fever. ESR was elevated (140 mm/h), and C-reactive protein level was 185 mg/L (normal range, ⱕ5 mg/L). There was polyclonal hypergammaglobulinemia (gamma globulin, 1.93 g/100 mL; normal range, 0.78 to 1.52 g/100 mL), whereas antinuclear factor and antiextractable nuclear antigen antibodies remained negative; in particular, anti-Ro/SSA and anti-La/ SSB antibodies were negative. Results of serum creatinine and urine analysis at that time were completely normal; there were no signs of type 1 renal tubular acidosis, hypokalemia, or diabetes insipidus. Abdominal computed tomography showed multiple bilateral hypodense lesions (13 to 17 Hounsfield units) in both kidneys and enlarged retroperitoneal lymphoid glands, suggestive of a lymphoproliferative disease or bilateral renal cell carcinoma (Fig 1). Subsequently, a CT-guided renal biopsy of a hypodense lesion in the right kidney was performed. Light microscopy of renal tissue showed diffuse interstitial infiltration by lymphocytes, histiocytes, and plasma cells, locally organized into a follicular pattern (Fig 2). Glomeruli had a normal appearance. Immunohistochemical staining confirmed the presence of immunoglobulin M– and immunoglobulin G–positive plasma cells with mild predominance of light chain–positive plasma cells. However, no evidence was found for malignancy or monotypic B-cell clone. The
From the Departments of Nephrology and Renal Transplantation and Pathology, University Hospitals Leuven, Belgium. Received March 14, 2005; accepted in revised form July 11, 2005. Originally published online as doi:10.1053/j.ajkd.2005.07.019 on September 14, 2005. Address reprint requests to Dirk R.J. Kuypers, MD, PhD, Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4605-0035$30.00/0 doi:10.1053/j.ajkd.2005.07.019
American Journal of Kidney Diseases, Vol 46, No 5 (November), 2005: E75-E80
e75
e76
OOMS ET AL
Fig 1. Abdominal computed tomographic scan shows bilateral multifocal renal parenchymal hypodense lesions and multiple retroperitoneal adenopathies.
diagnosis of pseudolymphoma was made, as can be encountered in some patients with bacterial pyelonephritis or other infectious disease and such systemic diseases as Sjögren syndrome. Further investigations did not show an infectious agent; therefore, treatment with methylprednisolone was started, resulting in prompt regression of inflammatory signs after a few days. After 1 month of treatment, the patient’s C-reactive protein level decreased to 48 mg/L, and ESR was 56 mm/h. After 2 months, a new abdominal computed tomographic scan was performed. This scan showed that hypodense lesions in both kidneys were stable in size, and retroperitoneal enlarged glands had disappeared. Three months later, the patient was lost to follow-up. On admission in November 2003, physical examination showed an apical grade-3 systolic heart murmur. There was very severe pitting edema of both legs, and central venous pressure was normal. The left eye protruded, with blue discoloration of the sclera. Laboratory tests showed normocytic anemia with a hemoglobin concentration of 11.7 g/dL (117 g/L) and normal reticulocyte count, white blood cell count of 11 ⫻ 103/L (11 ⫻ 109/L), platelet count of 350 ⫻ 103/L (350 ⫻ 109/L), and ESR of 113 mm/h. Serum creatinine concentration was 4.95 mg/dL (437 mol/L), blood urea nitrogen level was 126 mg/dL (45 mmol/L), and serum albumin concentration
was 2.2 g/dL (22 g/L). Liver enzyme levels were normal. There was hypercholesterolemia, with a total cholesterol level of 270 mg/dL (6.98 mmol/L) and low-density lipoprotein cholesterol level of 177 mg/dL (4.57 mmo/L). Urine sediment showed proteinuria and hematuria (277 red blood cells/L). Twenty-four–hour urine collection contained 13 g of protein, whereas calculated creatinine clearance was 11 mL/min (0.18 mL/s). Serum immunoglobulin and complement levels were normal. Serum electrophoresis showed an acute reactive process (albumin fraction, 37% [normal range, 56.8% to 68%]; ␣1-globulin fraction, 11.7% [normal range, 4.8% to 7.4%]; ␣2-globulin fraction, 19.5% [normal range, 7.3% to 12.3%]; -globulin fraction, 14.1% [normal range, 7.3% to 11.1%]), and serum immunofixation showed no evidence for a monoclonal fraction. Urine immunofixation did not detect paraprotein. Antinuclear factor was negative, and antineutrophil cytoplasmic autoantibody titer was 1/160, with normal antiproteinase 3 and antimyeloperoxidase concentrations. There was immunity for hepatitis B. Hepatitis C serological test result was negative. Because of persistent dyspnea, echocardiography was performed. The latter showed a hypocontractile left ventricle with diffuse hypokinesia (ejection fraction, 57%) and diastolic dysfunction, a moderate aortic (Björk-Shiley) prosthetic valve and mitral valve regurgitation, and pulmonary
SECONDARY RENAL AMYLOIDOSIS IN SJÖGREN SYNDROME
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Fig 2. First renal biopsy specimen shows diffuse interstitial infiltration by lymphocytes, histiocytes, and plasma cells locally organized into a follicular pattern. (Silver methenamine stain; original magnification 3 ⴛ20.)
hypertension (41 mm Hg). Abdominal ultrasound showed normal bipolar diameter of both kidneys (left, 11.7 cm; right, 11 cm); a 2.7-cm diameter mass was located in the right kidney. Compared with the computed tomographic scan of the abdomen in 1993, this lesion was stable in size. Because of the new-onset nephrotic syndrome of unknown cause in combination with acute renal failure, another renal biopsy was performed. Histological examination was very similar to that of 1993, with a dense mixed inflammatory interstitial infiltrate containing plasma cells, lymphocytes, and histiocytes (Fig 3). Again, immunohistochemistry showed no evidence of monoclonal cell expansion. Glomeruli were enlarged and showed fibrosis of the capsule. The mesangium of glomeruli was broadened because of eosinophilic hyaline deposits. Congo red staining of these hyaline deposits was positive; subsequently, the presence of AA amyloid was confirmed by means of the standard immunohistochemical technique using monoclonal AA antiserum (DakoCytomation, Glostrup, Denmark) at a dilution of 1/100. The diagnosis of a secondary AA-type amyloidosis caused by chronic inflammation of Sjögren syndrome was concluded. Treatment with oral methylprednisolone was started promptly at 1 mg/kg of body weight per day. After 4 weeks
of therapy, improvement in renal function was noticed, whereas proteinuria decreased significantly (serum creatinine level, from 5.0 to 3.7 mg/dL [442 to 327 mol/L]; creatinine clearance according to Cockcroft-Gault, from 11 to 20 mL/min [0.18 to 0.33 mL/s]; and proteinuria, from 13 to 6 g/24 h). Corticosteroid dosage was tapered very slowly, and 10 months later, a maintenance dose of 6 mg of prednisolone was adhered to. Partial remission of nephrotic syndrome was achieved with a decrease in proteinuria to protein of 3 g/d. Serum creatinine level improved to 2.6 mg/dL (230 mol/L), corresponding to a calculated creatinine clearance of 24 mL/min (0.4 mL/s). The reporting of this case was approved by the Institutional Review Board of the Faculty of Medicine, University of Leuven (ML No 3118).
DISCUSSION
We present a patient with Sjögren syndrome in whom pseudolymphoma of the kidneys was diagnosed in 1993. Ten years later, in 2003, he presented with nephrotic syndrome and renal insufficiency caused by secondary (AA) renal
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OOMS ET AL
Fig 3. Second biopsy specimen shows dense mixed inflammatory interstitial infiltrate containing plasma cells, lymphocytes, and histiocytes with hyaline deposits in glomeruli and vessel walls. Congo red staining of these hyaline deposits was positive. (Silver methenamine stain; original magnification 3 ⴛ10.)
amyloidosis superimposed on chronic tubulointerstitial nephritis. Sjögren syndrome is a chronic inflammatory disorder characterized by polyclonal B-cell activation, as well as lymphocytic infiltration of exocrine glands, especially the lacrimal and salivary glands. Because of this B-cell activation, malignant lymphoproliferative disorders occur with a greater frequency in patients with Sjögren syndrome.2 When B cells are pleomorphic, but fail to meet criteria for true malignancy, the term pseudolymphoma often is applied. This may present as lymphadenopathy or functional impairment of the affected organ, such as kidney or lung. Lymphocytic infiltration in patients with Sjögren syndrome can affect the kidneys, resulting in interstitial nephritis. Glomerular involvement is much less common in patients with Sjögren syndrome, and the exact pathogenesis is unclear. The prevalence of renal involvement in patients with Sjögren syndrome is not well known, but overall, occurs infrequently.3-5
Primary Sjögren syndrome was diagnosed in this patient in 1985 in accordance with the current American-European revised rules for classification of Sjögren syndrome.1 Between 1985 and 1989, he experienced several documented relapses of scleritis, with fever and chronic inflammation assessed by means of laboratory biochemistry. The patient had severe biopsy-proven chronic interstitial nephritis since 1993 that was not treated long enough because of patient noncompliance and skipping of scheduled follow-up visits. Consequently, the long-standing chronic inflammation triggered the development of secondary (AA) amyloidosis with renal and suspected cardiac involvement. AA amyloidosis is characterized by extracellular tissue deposition of serum amyloid A fibrils that,6 if left untreated, leads to serious disease with significant mortality caused by end-stage renal disease, infection, heart failure, or bowel perforation.7 The risk for developing systemic AA amyloidosis is related to the continuous and subclinical
SECONDARY RENAL AMYLOIDOSIS IN SJÖGREN SYNDROME
inflammation that occurs during attack-free periods and, consequently, the magnitude and persistency of elevated serum amyloid A levels. The clinical course of this patient with recurrent episodes of documented disease activity, a history of noncompliance with corticosteroid maintenance therapy, and the final presentation in 2003 with nephrotic syndrome are suggestive of a causal relationship between persistent Sjögren syndrome–associated inflammation and the development of renal AA amyloidosis. Unfortunately, serum amyloid A levels were not determined. Unique in this setting is the concurrent finding of persistent chronic tubulointerstitial nephritis and AA amyloid depositions in the repeated biopsy specimen. Because of the latter finding and the clinical history, we assume that the chronic interstitial nephritis itself, next to extrarenal persistent disease activity, was the stimulus for the development of renal AA amyloidosis. Because the preferred therapy for AA amyloidosis still is treatment of the underlying inflammatory disease,8 our patient was treated with corticosteroids and achieved partial remission of nephrotic syndrome and improvement in renal function, probably predominantly through resolving the interstitial inflammatory component. We suggest that therapeutic control of the concurrent tubulointerstitial parenchymatous inflammation might have had a partially beneficial role in the clinical course of Sjögren syndrome–related renal AA amyloidosis. This unusual presentation indicates that a repeated renal biopsy seems warranted in patients with long-standing Sjögren disease who develop renal insufficiency or (nephrotic-range) proteinuria. The occurrence of amyloidosis in patients with primary Sjögren syndrome remains rare. In previous cases, amyloidosis was localized in the dermis,9,10 lung,11-14 tongue,15 or breasts.16 Only 1 report showed the concomitant diagnosis of primary Sjögren syndrome and systemic AL amyloidosis.17 The occurrence of amyloidomas (amyloidosis presenting as a tumor) in patients with Sjögren syndrome is better documented. Sites of amyloidomas in these patients included lung, tongue, neck, bladder, esophagus, and lower limbs.18 To our knowledge, this is the first report of a patient with long-standing primary Sjögren syn-
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drome and secondary renal (AA) amyloidosis resulting in a nephrotic syndrome. Primary Sjögren syndrome therefore should be regarded as a novel predisposing condition for renal AA amyloidosis. REFERENCES 1. Vitali C, Bombardieri S, Jonsson R, et al: Classification criteria for Sjögren’s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554-558, 2002 2. Mariette X: Lymphomas in patients with Sjögren’s syndrome: Review of the literature and physiopathologic hypothesis. Leuk Lymphoma 33:93-99, 1999 3. Goules A, Masouridi S, Tzioufas AG, Ioannidis JP, Skopouli FN, Moutsopoulos HM: Clinically significant and biopsy-documented renal involvement in primary Sjögren syndrome. Medicine (Baltimore) 79:241-249, 2000 4. Bossini N, Savoldi S, Franceschini F, et al: Clinical and morphological features of kidney involvement in primary Sjögren’s syndrome. Nephrol Dial Transplant 16:23282336, 2001 5. Kwon YJ, Park JH, Kim SW, et al: Sjögren’s syndrome with acute renal failure. J Korean Med Sci 13:665-669, 1998 6. Glenner GG: Amyloid deposits and amyloidosis. The beta-fibrilloses. N Engl J Med 302:1333-1343, 1980 7. Tanaka F, Migita K, Honda S, et al: Clinical outcome and survival of secondary (AA) amyloidosis. Clin Exp Rheumatol 21:343-346, 2003 8. Gillmore JD, Lovat LB, Persey MR, et al: Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 358:24-29, 2001 9. Pablos JL, Cogolludo V, Pinedo F, Carreire PE: Subcutaneous nodular amyloidosis in Sjögren’s syndrome. Scand J Rheumatol 22:250-251, 1993 10. Inazumi T, Hakuno M, Yamada H, et al: Characterisation of the amyloid fibril from primary localized cutaneous nodular amyloidosis associated with Sjögren’s syndrome. Dermatology 189:125-128, 1994 11. Kobayashi H, Matsuoka R, Kitamura S, Tsunoda N, Saito K: Sjögren’s syndrome with multiple bullae and pulmonary nodular amyloidosis. Chest 94:438-440, 1988 12. Milburn JM, Kay D, Ridpat C: Pulmonary nodular amyloidosis in a patient with Sjögren’s syndrome diagnosed by transthoracic biopsy. J La State Med Soc 146:395-398, 1994 13. Wong BC, Wong KL, Ip MS, Wang EP, Chan KW, Cheng LC: Sjögren’s syndrome with amyloid A presenting as multiple pulmonary nodules. J Rheumatol 21:165-167, 1994 14. Srinivas P, Liam CK, Jayaram G: Localised nodular pulmonary amyloidosis in a patient with sicca syndrome. Med J Malaysia 55:385-387, 2000 15. Haraguchi H, Ohashi K, Yamada M, Hasegawa M, Maeda S, Komatsuzaki A: Primary localized nodular tongue amyloidosis associated with Sjögren’s syndrome. ORL J Otorhinolaryngol Relat Spec 1:60-63, 1997 16. Kambouchner M, Godmer P, Guillevin L, Raphael M, Droz D, Martin A: Low grade marginal zone B cell lym-
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syndrome and systemic AL amyloidosis. Ann Rheum Dis 60:694-695, 2001 18. Ideura H, Tsukada Y, Maezawa A, Ueki K, Nojima Y, Naruse T: Sjögren’s syndrome and multiple amyloidomas. J Rheumatol 27:1325-1326, 2000